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1. Astrogliosis and neuroinflammation underlie scoliosis upon cilia dysfunction

Author: Morgane Djebar, Isabelle Anselme, Guillaume Pezeron, Pierre-Luc Bardet, Yasmine Cantaut-Belarif, Alexis Eschstruth, Diego López-Santos, Hélène Le Ribeuz, Arnim Jenett, Hanane Khoury, Joelle Veziers, Caroline Parmentier, Aurélie Hirschler, Christine Carapito, Ruxandra Bachmann-Gagescu, Sylvie Schneider-Maunoury, and Christine Vesque
Subjects: scoliosis, cilia, rpgrip1l, astrogliosis, inflammation, urotensin peptides, Medicine, Science, Biology (General), QH301-705.5
Abstract: Cilia defects lead to scoliosis in zebrafish, but the underlying pathogenic mechanisms are poorly understood and may diverge depending on the mutated gene. Here, we dissected the mechanisms of scoliosis onset in a zebrafish mutant for the rpgrip1l gene encoding a ciliary transition zone protein. rpgrip1l mutant fish developed scoliosis with near-total penetrance but asynchronous onset in juveniles. Taking advantage of this asynchrony, we found that curvature onset was preceded by ventricle dilations and was concomitant to the perturbation of Reissner fiber polymerization and to the loss of multiciliated tufts around the subcommissural organ. Rescue experiments showed that Rpgrip1l was exclusively required in foxj1a-expressing cells to prevent axis curvature. Genetic interactions investigations ruled out Urp1/2 levels as a main driver of scoliosis in rpgrip1 mutants. Transcriptomic and proteomic studies identified neuroinflammation associated with increased Annexin levels as a potential mechanism of scoliosis development in rpgrip1l juveniles. Investigating the cell types associated with annexin2 over-expression, we uncovered astrogliosis, arising in glial cells surrounding the diencephalic and rhombencephalic ventricles just before scoliosis onset and increasing with time in severity. Anti-inflammatory drug treatment reduced scoliosis penetrance and severity and this correlated with reduced astrogliosis and macrophage/microglia enrichment around the diencephalic ventricle. Mutation of the cep290 gene encoding another transition zone protein also associated astrogliosis with scoliosis. Thus, we propose astrogliosis induced by perturbed ventricular homeostasis and associated with immune cell activation as a novel pathogenic mechanism of zebrafish scoliosis caused by cilia dysfunction.
Published: 2024
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2. Centriole Translational Planar Polarity in Monociliated Epithelia

Author: Antoine Donati, Sylvie Schneider-Maunoury, and Christine Vesque
Subjects: planar cell polarity, translational polarity, epithelial polarity, cilia, basal body, centriole, Cytology, QH573-671
Abstract: Ciliated epithelia are widespread in animals and play crucial roles in many developmental and physiological processes. Epithelia composed of multi-ciliated cells allow for directional fluid flow in the trachea, oviduct and brain cavities. Monociliated epithelia play crucial roles in vertebrate embryos, from the establishment of left–right asymmetry to the control of axis curvature via cerebrospinal flow motility in zebrafish. Cilia also have a central role in the motility and feeding of free-swimming larvae in a variety of marine organisms. These diverse functions rely on the coordinated orientation (rotational polarity) and asymmetric localization (translational polarity) of cilia and of their centriole-derived basal bodies across the epithelium, both being forms of planar cell polarity (PCP). Here, we review our current knowledge on the mechanisms of the translational polarity of basal bodies in vertebrate monociliated epithelia from the molecule to the whole organism. We highlight the importance of live imaging for understanding the dynamics of centriole polarization. We review the roles of core PCP pathways and of apicobasal polarity proteins, such as Par3, whose central function in this process has been recently uncovered. Finally, we emphasize the importance of the coordination between polarity proteins, the cytoskeleton and the basal body itself in this highly dynamic process.
Published: 2024
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3. A multiscale mathematical model of cell dynamics during neurogenesis in the mouse cerebral cortex

Author: Marie Postel, Alice Karam, Guillaume Pézeron, Sylvie Schneider-Maunoury, and Frédérique Clément
Subjects: Multiscale mathematical modeling, Neurogenesis, Development of the cerebral cortex, Cell dynamics, Neural progenitors, Mouse mutant for Ftm/Rpgrip1l, Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract: Abstract Background Neurogenesis in the murine cerebral cortex involves the coordinated divisions of two main types of progenitor cells, whose numbers, division modes and cell cycle durations set up the final neuronal output. To understand the respective roles of these factors in the neurogenesis process, we combine experimental in vivo studies with mathematical modeling and numerical simulations of the dynamics of neural progenitor cells. A special focus is put on the population of intermediate progenitors (IPs), a transit amplifying progenitor type critically involved in the size of the final neuron pool. Results A multiscale formalism describing IP dynamics allows one to track the progression of cells along the subsequent phases of the cell cycle, as well as the temporal evolution of the different cell numbers. Our model takes into account the dividing apical progenitors (AP) engaged into neurogenesis, both neurogenic and proliferative IPs, and the newborn neurons. The transfer rates from one population to another are subject to the mode of division (proliferative, or neurogenic) and may be time-varying. The model outputs are successfully fitted to experimental cell numbers from mouse embryos at different stages of cortical development, taking into account IPs and neurons, in order to adjust the numerical parameters. We provide additional information on cell kinetics, such as the mitotic and S phase indexes, and neurogenic fraction. Conclusions Applying the model to a mouse mutant for Ftm/Rpgrip1l, a gene involved in human ciliopathies with severe brain abnormalities, reveals a shortening of the neurogenic period associated with an increased influx of newborn IPs from apical progenitors at mid-neurogenesis. Our model can be used to study other mouse mutants with cortical neurogenesis defects and can be adapted to study the importance of progenitor dynamics in cortical evolution and human diseases.
Published: 2019
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4. Cilia, ciliopathies and hedgehog-related forebrain developmental disorders

Author: Abraham Andreu-Cervera, Martin Catala, and Sylvie Schneider-Maunoury
Subjects: Forebrain, Cerebral cortex, Brain development, Primary cilia, Sonic hedgehog, Gli transcription factor, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Development of the forebrain critically depends on the Sonic Hedgehog (Shh) signaling pathway, as illustrated in humans by the frequent perturbation of this pathway in holoprosencephaly, a condition defined as a defect in the formation of midline structures of the forebrain and face. The Shh pathway requires functional primary cilia, microtubule-based organelles present on virtually every cell and acting as cellular antennae to receive and transduce diverse chemical, mechanical or light signals. The dysfunction of cilia in humans leads to inherited diseases called ciliopathies, which often affect many organs and show diverse manifestations including forebrain malformations for the most severe forms.The purpose of this review is to provide the reader with a framework to understand the developmental origin of the forebrain defects observed in severe ciliopathies with respect to perturbations of the Shh pathway. We propose that many of these defects can be interpreted as an imbalance in the ratio of activator to repressor forms of the Gli transcription factors, which are effectors of the Shh pathway.We also discuss the complexity of ciliopathies and their relationships with forebrain disorders such as holoprosencephaly or malformations of cortical development, and emphasize the need for a closer examination of forebrain defects in ciliopathies, not only through the lens of animal models but also taking advantage of the increasing potential of the research on human tissues and organoids.
Published: 2021
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5. A transient role of the ciliary gene Inpp5e in controlling direct versus indirect neurogenesis in cortical development

Author: Kerstin Hasenpusch-Theil, Christine Laclef, Matt Colligan, Eamon Fitzgerald, Katherine Howe, Emily Carroll, Shaun R Abrams, Jeremy F Reiter, Sylvie Schneider-Maunoury, and Thomas Theil
Subjects: Inpp5e, Gli3, primary cilium, neurogenesis, cortex, Medicine, Science, Biology (General), QH301-705.5
Abstract: During the development of the cerebral cortex, neurons are generated directly from radial glial cells or indirectly via basal progenitors. The balance between these division modes determines the number and types of neurons formed in the cortex thereby affecting cortical functioning. Here, we investigate the role of primary cilia in controlling the decision between forming neurons directly or indirectly. We show that a mutation in the ciliary gene Inpp5e leads to a transient increase in direct neurogenesis and subsequently to an overproduction of layer V neurons in newborn mice. Loss of Inpp5e also affects ciliary structure coinciding with reduced Gli3 repressor levels. Genetically restoring Gli3 repressor rescues the decreased indirect neurogenesis in Inpp5e mutants. Overall, our analyses reveal how primary cilia determine neuronal subtype composition of the cortex by controlling direct versus indirect neurogenesis. These findings have implications for understanding cortical malformations in ciliopathies with INPP5E mutations.
Published: 2020
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6. MKS-NPHP module proteins control ciliary shedding at the transition zone.

Author: Delphine Gogendeau, Michel Lemullois, Pierrick Le Borgne, Manon Castelli, Anne Aubusson-Fleury, Olivier Arnaiz, Jean Cohen, Christine Vesque, Sylvie Schneider-Maunoury, Khaled Bouhouche, France Koll, and Anne-Marie Tassin
Subjects: Biology (General), QH301-705.5
Abstract: Ciliary shedding occurs from unicellular organisms to metazoans. Although required during the cell cycle and during neurogenesis, the process remains poorly understood. In all cellular models, this phenomenon occurs distal to the transition zone (TZ), suggesting conserved molecular mechanisms. The TZ module proteins (Meckel Gruber syndrome [MKS]/Nephronophtysis [NPHP]/Centrosomal protein of 290 kDa [CEP290]/Retinitis pigmentosa GTPase regulator-Interacting Protein 1-Like Protein [RPGRIP1L]) are known to cooperate to establish TZ formation and function. To determine whether they control deciliation, we studied the function of 5 of them (Transmembrane protein 107 [TMEM107], Transmembrane protein 216 [TMEM216], CEP290, RPGRIP1L, and NPHP4) in Paramecium. All proteins are recruited to the TZ of growing cilia and localize with 9-fold symmetry at the level of the most distal part of the TZ. We demonstrate that depletion of the MKS2/TMEM216 and TMEM107 proteins induces constant deciliation of some cilia, while depletion of either NPHP4, CEP290, or RPGRIP1L prevents Ca2+/EtOH deciliation. Our results constitute the first evidence for a role of conserved TZ proteins in deciliation and open new directions for understanding motile cilia physiology.
Published: 2020
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7. RPGRIP1L is required for stabilizing epidermal keratinocyte adhesion through regulating desmoglein endocytosis.

Author: Yeon Ja Choi, Christine Laclef, Ning Yang, Abraham Andreu-Cervera, Joshua Lewis, Xuming Mao, Li Li, Elizabeth R Snedecor, Ken-Ichi Takemaru, Chuan Qin, Sylvie Schneider-Maunoury, Kenneth R Shroyer, Yusuf A Hannun, Peter J Koch, Richard A Clark, Aimee S Payne, Andrew P Kowalczyk, and Jiang Chen
Subjects: Genetics, QH426-470
Abstract: Cilia-related proteins are believed to be involved in a broad range of cellular processes. Retinitis pigmentosa GTPase regulator interacting protein 1-like (RPGRIP1L) is a ciliary protein required for ciliogenesis in many cell types, including epidermal keratinocytes. Here we report that RPGRIP1L is also involved in the maintenance of desmosomal junctions between keratinocytes. Genetically disrupting the Rpgrip1l gene in mice caused intraepidermal blistering, primarily between basal and suprabasal keratinocytes. This blistering phenotype was associated with aberrant expression patterns of desmosomal proteins, impaired desmosome ultrastructure, and compromised cell-cell adhesion in vivo and in vitro. We found that disrupting the RPGRIP1L gene in HaCaT cells, which do not form primary cilia, resulted in mislocalization of desmosomal proteins to the cytoplasm, suggesting a cilia-independent function of RPGRIP1L. Mechanistically, we found that RPGRIP1L regulates the endocytosis of desmogleins such that RPGRIP1L-knockdown not only induced spontaneous desmoglein endocytosis, as determined by AK23 labeling and biotinylation assays, but also exacerbated EGTA- or pemphigus vulgaris IgG-induced desmoglein endocytosis. Accordingly, inhibiting endocytosis with dynasore or sucrose rescued these desmosomal phenotypes. Biotinylation assays on cell surface proteins not only reinforced the role of RPGRIP1L in desmoglein endocytosis, but also suggested that RPGRIP1L may be more broadly involved in endocytosis. Thus, data obtained from this study advanced our understanding of the biological functions of RPGRIP1L by identifying its role in the cellular endocytic pathway.
Published: 2019
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8. An in vivo translation-reporter system for the study of protein synthesis in zebrafish embryos

Author: Inês Garcez Palha, Isabelle Anselme, Sylvie Schneider-Maunoury, and François Giudicelli
Subjects: SPoT, TimeStamp, Local translation, Neuron, Zebrafish, Science, Biology (General), QH301-705.5
Abstract: Control of gene expression at the translation level is increasingly regarded as a key feature in many biological processes. Simple, inexpensive and reliable procedures to visualize sites of protein production are required to allow observation of the spatiotemporal patterns of mRNA translation at subcellular resolution. We present a method, named SPoT (for Subcellular Patterns of Translation), developed upon the original TimeStamp technique ( Lin et al., 2008), consisting in the expression of a fluorescent protein fused to a tagged, self-cleavable protease domain. The addition of a cell-permeable protease inhibitor instantly stabilizes newly produced tagged protein allowing us to distinguish recently synthesized proteins from pre-existing ones. After a brief protease inhibitor treatment, the ratio of tagged versus non-tagged forms is highest at sites where proteins are the most recent, i.e. sites of synthesis. Therefore, by comparing tagged and non-tagged proteins it is possible to spotlight sites of translation. By specifically expressing the SPoT cassette in neurons of transgenic zebrafish embryos, we reveal sites of neuronal protein synthesis in diverse cellular compartments during early development.
Published: 2018
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9. Initiation of cyp26a1 Expression in the Zebrafish Anterior Neural Plate by a Novel Cis-Acting Element.

Author: Chunhong Chen, Aline Stedman, Emmanuelle Havis, Isabelle Anselme, Daria Onichtchouk, François Giudicelli, and Sylvie Schneider-Maunoury
Subjects: Medicine, Science
Abstract: Early patterning of the vertebrate neural plate involves a complex hierarchy of inductive interactions orchestrated by signalling molecules and their antagonists. The morphogen retinoic acid, together with the Cyp26 enzymes which degrade it, play a central role in this process. The cyp26a1 gene expressed in the anterior neural plate thus contributes to the fine modulation of the rostrocaudal retinoic acid gradient. Despite this important role of cyp26a1 in early brain formation, the mechanisms that control its expression in the anterior neural plate are totally unknown. Here, we present the isolation of a 310-base-pair DNA element adjacent to cyp26a1 promoter, displaying enhancer activity restricted to the anterior neural plate of the zebrafish gastrula. We show that unlike that of cyp26a1, expression driven by this cyp26a1 anterior neural plate element (cANE) is independent of retinoic acid. Through deletion analysis, we identify a 12-nucleotide motif essential for cANE activity. A consensus bipartite binding site for SoxB:Oct transcription factors overlaps with this motif. Mutational analysis suggests that SoxB binding is essential for its activity. We discuss the contribution of this study to the elucidation of the regulatory hierarchy involved in early neural plate patterning.
Published: 2016
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10. Whole embryo chromatin immunoprecipitation protocol for the in vivo study of zebrafish development

Author: Emmanuelle Havis, Isabelle Anselme, and Sylvie Schneider-Maunoury
Subjects: Biology (General), QH301-705.5
Published: 2006
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11. Functional analysis of the NUP98-CCDC28A fusion protein

Author: Arnaud Petit, Christine Ragu, Gwendoline Soler, Chris Ottolenghi, Caroline Schluth, Isabelle Radford-Weiss, Sylvie Schneider-Maunoury, Isabelle Callebaut, Nicole Dastugue, Harry A. Drabkin, Olivier A. Bernard, Serge Romana, and Virginie Penard-Lacronique
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: Background The nucleoporin gene NUP98 is rearranged in more than 27 chromosomal abnormalities observed in childhood and adult, de novo and therapy-related acute leukemias of myeloid and T-lymphoid origins, resulting in the creation of fusion genes and the expression of chimeric proteins. We report here the functional analysis of the NUP98-coiled-coil domain-containing protein 28A (NUP98-CCDC28A) fusion protein, expressed as the consequence of a recurrent t(6;11)(q24.1;p15.5) translocation.Design and Methods To gain insight into the function of the native CCDC28A gene, we collected information on any differential expression of CCDC28A among normal hematologic cell types and within subgroups of acute leukemia. To assess the in vivo effects of the NUP98-CCDC28A fusion, NUP98-CCDC28A or full length CCDC28A were retrovirally transduced into primary murine bone marrow cells and transduced cells were next transplanted into sub-lethally irradiated recipient mice.Results Our in silico analyses supported a contribution of CCDC28A to discrete stages of murine hematopoietic development. They also suggested selective enrichment of CCDC28A in the French-American-British M6 class of human acute leukemia. Primary murine hematopoietic progenitor cells transduced with NUP98-CCDC28A generated a fully penetrant and transplantable myeloproliferative neoplasm-like myeloid leukemia and induced selective expansion of granulocyte/macrophage progenitors in the bone marrow of transplanted recipients, showing that NUP98-CCDC28A promotes the proliferative capacity and self-renewal potential of myeloid progenitors. In addition, the transformation mediated by NUP98-CCDC28A was not associated with deregulation of the Hoxa-Meis1 pathway, a feature shared by a diverse set of NUP98 fusions.Conclusions Our results demonstrate that the recurrent NUP98-CCDC28A is an oncogene that induces a rapid and transplantable myeloid neoplasm in recipient mice. They also provide additional evidence for an alternative leukemogenic mechanism for NUP98 oncogenes.
Published: 2012
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12. Rpgrip1l controls ciliary gating by ensuring the proper amount of Cep290 at the vertebrate transition zone

Author: Hemant Khanna, Christoph Gerhardt, Sylvie Schneider-Maunoury, Christine Vesque, Renate Dildrop, Antonia Wiegering, Laboratoire de Biologie du Développement [Paris] (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Morphogénèse du Cerveau des Vertébrés = Morphogenesis of the vertebrate brain (LBD-E10), Institut National de la Santé et de la Recherche Médicale (INSERM)-Laboratoire de Biologie du Développement [Paris] (LBD), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Laboratoire de Biologie du Développement [IBPS] (LBD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Laboratoire de Biologie du Développement [IBPS] (LBD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and HAL-SU, Gestionnaire
Subjects: Axoneme, [SDV]Life Sciences [q-bio], Cell Cycle Proteins, Gating, Ciliopathies, 03 medical and health sciences, Mice, 0302 clinical medicine, Antigens, Neoplasm, biology.animal, Animals, Humans, Cilia, Molecular Biology, 030304 developmental biology, Adaptor Proteins, Signal Transducing, Centrioles, 0303 health sciences, biology, Cilium, Vertebrate, Cell Biology, Articles, Basal Bodies, [SDV] Life Sciences [q-bio], Cytoskeletal Proteins, HEK293 Cells, RPGRIP1L, Mutation, NIH 3T3 Cells, Neuroscience, 030217 neurology & neurosurgery, Signal Transduction
Abstract: International audience; A range of severe human diseases called ciliopathies are caused by the dysfunction of primary cilia. Primary cilia are cytoplasmic protrusions consisting of the basal body (BB), the axoneme and the transition zone (TZ). The BB is a modified mother centriole from which the axoneme, the microtubule-based ciliary scaffold, is formed. At the proximal end of the axoneme, the TZ functions as the ciliary gate governing ciliary protein entry and exit. Since ciliopathies often develop due to mutations in genes encoding proteins that localise to the TZ, the understanding of the mechanisms underlying TZ function is of eminent importance. Here, we show that the ciliopathy protein Rpgrip1l governs ciliary gating by ensuring the proper amount of Cep290 at the vertebrate TZ. Further, we identified the flavonoid eupatilin as a potential agent to tackle ciliopathies caused by mutations in RPGRIP1L as it rescues ciliary gating in the absence of Rpgrip1l.
Published: 2021

13. Cilia, ciliopathies and hedgehog-related forebrain developmental disorders

Author: Abraham Andreu-Cervera, Martin Catala, Sylvie Schneider-Maunoury, Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universidad Miguel Hernández [Elche] (UMH), Fondation ARC pour la Recherche sur le Cancer, Fondation pour la Recherche Médicale, Gestionnaire, HAL Sorbonne Université 5, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Developmental Disabilities, RPGRIP1L, Ciliopathies, Craniofacial Abnormalities, 0302 clinical medicine, Holoprosencephaly, Primary cilia, Cerebellum, Eye Abnormalities, Sonic hedgehog, Encephalocele, Polycystic Kidney Diseases, Cilium, Brain, Gene Expression Regulation, Developmental, Kidney Diseases, Cystic, Cerebral cortex, Brain development, 3. Good health, Neurology, Gli transcription factor, Microcephaly, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Retinitis Pigmentosa, Ciliary Motility Disorders, Signal Transduction, Ciliopathy, Biology, Zinc Finger Protein Gli2, Zinc Finger Protein GLI1, Retina, lcsh:RC321-571, 03 medical and health sciences, Prosencephalon, Zinc Finger Protein Gli3, medicine, Humans, Abnormalities, Multiple, Hedgehog Proteins, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cilia, Hedgehog, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, medicine.disease, 030104 developmental biology, Forebrain, biology.protein, Neuroscience, 030217 neurology & neurosurgery
Abstract: Development of the forebrain critically depends on the Sonic Hedgehog (Shh) signaling pathway, as illustrated in humans by the frequent perturbation of this pathway in holoprosencephaly, a condition defined as a defect in the formation of midline structures of the forebrain and face. The Shh pathway requires functional primary cilia, microtubule-based organelles present on virtually every cell and acting as cellular antennae to receive and transduce diverse chemical, mechanical or light signals. The dysfunction of cilia in humans leads to inherited diseases called ciliopathies, which often affect many organs and show diverse manifestations including forebrain malformations for the most severe forms. The purpose of this review is to provide the reader with a framework to understand the developmental origin of the forebrain defects observed in severe ciliopathies with respect to perturbations of the Shh pathway. We propose that many of these defects can be interpreted as an imbalance in the ratio of activator to repressor forms of the Gli transcription factors, which are effectors of the Shh pathway. We also discuss the complexity of ciliopathies and their relationships with forebrain disorders such as holoprosencephaly or malformations of cortical development, and emphasize the need for a closer examination of forebrain defects in ciliopathies, not only through the lens of animal models but also taking advantage of the increasing potential of the research on human tissues and organoids., This work was supported by funding to SSM from the Fondation pour la Recherche Médicale (Equipe FRM EQU201903007943) and from the Fondation ARC (PJA 20171206591).
Published: 2020

14. Primary cilium-dependent cAMP/PKA signaling at the centrosome regulates neuronal migration

Author: Christine Métin, Julie Stoufflet, Isabelle Caillé, Alain Trembleau, Coralie Fouquet, Sylvie Schneider-Maunoury, Mohamed Doulazmi, Pierre Vincent, Maxime Chaulet, Caroline Dubacq, Gestionnaire, HAL Sorbonne Université 5, Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Institut du Fer à Moulin, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Laboratoire de Biologie du Développement [IBPS] (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Laboratoire de Biologie du Développement [Paris] (LBD)
Subjects: Adenosine, Adenylate kinase, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, Live cell imaging, Organelle, Cilia, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Protein kinase A, Research Articles, 030304 developmental biology, Centrosome, 0303 health sciences, Gene knockdown, Multidisciplinary, Chemistry, Cilium, SciAdv r-articles, Cell Biology, Cyclic AMP-Dependent Protein Kinases, Embryonic stem cell, Cell biology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], sense organs, 030217 neurology & neurosurgery, Research Article
Abstract: The primary cilium regulates neuronal migration via cyclic AMP production activating protein kinase A at the centrosome., The primary cilium (PC) is a small centrosome-assembled organelle, protruding from the surface of most eukaryotic cells. It plays a key role in cell migration, but the underlying mechanisms are unknown. Here, we show that the PC regulates neuronal migration via cyclic adenosine 3’-5’ monosphosphate (cAMP) production activating centrosomal protein kinase A (PKA). Biosensor live imaging revealed a periodic cAMP hotspot at the centrosome of embryonic, postnatal, and adult migrating neurons. Genetic ablation of the PC, or knockdown of ciliary adenylate cyclase 3, caused hotspot disappearance and migratory defects, with defective centrosome dynamics and altered nucleokinesis. Delocalization of PKA from the centrosome phenocopied the migratory defects. Our results show that the PC and centrosome form a single cAMP signaling unit dynamically regulating migration, further highlighting the centrosome as a signaling hub.
Published: 2020

15. A transient role of the ciliary gene Inpp5e in controlling direct versus indirect neurogenesis in cortical development

Author: Christine Laclef, Katherine Howe, Matt Colligan, Emily Carroll, Thomas Theil, Sylvie Schneider-Maunoury, Shaun R Abrams, Jeremy F. Reiter, Kerstin Hasenpusch-Theil, and Eamon Fitzgerald
Subjects: Male, 0301 basic medicine, Mouse, QH301-705.5, Science, Neurogenesis, Repressor, Gli3, Biology, Ciliopathies, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Cortex (anatomy), INPP5E, GLI3, medicine, Animals, Biology (General), Cerebral Cortex, General Immunology and Microbiology, General Neuroscience, Cilium, General Medicine, Phosphoric Monoester Hydrolases, Cell biology, cortex, 030104 developmental biology, medicine.anatomical_structure, Cerebral cortex, Inpp5e, Medicine, Female, 030217 neurology & neurosurgery, Research Article, Developmental Biology, primary cilium
Abstract: During the development of the cerebral cortex, neurons are generated directly from radial glial cells or indirectly via basal progenitors. The balance between these division modes determines the number and types of neurons formed in the cortex thereby affecting cortical functioning. Here, we investigate the role of primary cilia in controlling the decision between forming neurons directly or indirectly. We show that a mutation in the ciliary geneInpp5eleads to a transient increase in direct neurogenesis and subsequently to an overproduction of layer V neurons in newborn mice. Loss ofInpp5ealso affects ciliary structure coinciding with reduced Gli3 repressor levels. Genetically restoring Gli3 repressor rescues the decreased indirect neurogenesis inInpp5emutants. Overall, our analyses reveal how primary cilia determine neuronal subtype composition of the cortex by controlling direct versus indirect neurogenesis. These findings have implications for understanding cortical malformations in ciliopathies withINPP5Emutations.
Published: 2020

16. A transient role of primary cilia in controlling direct versus indirect neurogenesis in the developing cerebral cortex

Author: Christine Laclef, Thomas Theil, Matt Colligan, Kerstin Hasenpusch-Theil, Sylvie Schneider-Maunoury, Katherine Howe, Emily Carroll, Eamon Fitzgerald, Shaun R Abrams, and Jeremy F. Reiter
Subjects: 0303 health sciences, Cilium, 030302 biochemistry & molecular biology, Neurogenesis, Repressor, Biology, Ciliopathies, Cell biology, 03 medical and health sciences, medicine.anatomical_structure, Cerebral cortex, Cortex (anatomy), GLI3, medicine, PI3K/AKT/mTOR pathway, 030304 developmental biology
Abstract: During the development of the cerebral cortex, neurons are generated directly from radial glial cells or indirectly via basal progenitors. The balance between these division modes determines the number and types of neurons formed in the cortex thereby affecting cortical functioning. Here, we investigate the role of primary cilia in this process. We show that a mutation in the ciliary geneInpp5eleads to a transient increase in direct neurogenesis and subsequently to an overproduction of layer V neurons in newborn mice. Loss ofInpp5ealso affects ciliary structure coinciding with increased Akt and mTOR signalling and reduced Gli3 repressor levels. Genetically re-storing Gli3 repressor rescues the decreased indirect neurogenesis inInpp5emutants. Overall, our analyses reveal how primary cilia determine neuronal subtype composition of the cortex by controlling direct vs indirect neurogenesis. These findings have implications for understanding cortical malformations in ciliopathies withINPP5Emutations.
Published: 2020
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17. Rpgrip1l controls ciliary gating by ensuring the proper amount of Cep290 at the vertebrate transition zone

Author: Christoph Gerhardt, Antonia Wiegering, Sylvie Schneider-Maunoury, Christine Vesque, and Renate Dildrop
Subjects: Axoneme, Ciliopathy, Microtubule, Cytoplasm, Cilium, medicine, Basal body, Gating, Biology, medicine.disease, Ciliopathies, Cell biology
Abstract: A range of severe human diseases called ciliopathies are caused by the dysfunction of primary cilia. Primary cilia are cytoplasmic protrusions consisting of the basal body (BB), the axoneme and the transition zone (TZ). The BB is a modified mother centriole from which the axoneme, the microtubule-based ciliary scaffold, is formed. At the proximal end of the axoneme, the TZ functions as the ciliary gate governing ciliary protein entry and exit. Since ciliopathies often develop due to mutations in genes encoding proteins that localise to the TZ, the understanding of the mechanisms underlying TZ function is of eminent importance. Here, we show that the ciliopathy protein Rpgrip1l governs ciliary gating by ensuring the proper amount of Cep290 at the vertebrate TZ. Further, we identified the flavonoid eupatilin as a potential agent to tackle ciliopathies caused by mutations in RPGRIP1L as it rescues ciliary gating in the absence of Rpgrip1l.
Published: 2020
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18. RPGRIP1L is required for stabilizing epidermal keratinocyte adhesion through regulating desmoglein endocytosis

Author: Yusuf A. Hannun, Christine Laclef, Kenneth R. Shroyer, Peter Koch, Ning Yang, Sylvie Schneider-Maunoury, Andrew P. Kowalczyk, Abraham Andreu-Cervera, Xuming Mao, Jiang Chen, Richard A.F. Clark, Chuan Qin, Ken-Ichi Takemaru, Yeon Ja Choi, Joshua D. Lewis, Elizabeth R. Snedecor, Aimee S. Payne, Li Li, Stony Brook University [SUNY] (SBU), State University of New York (SUNY), Laboratoire de Biologie du Développement [Paris] (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Emory University [Atlanta, GA], University of Pennsylvania [Philadelphia], University of Colorado [Denver], Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, and University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]
Subjects: Keratinocytes, Cancer Research, Endocytic cycle, Cell Membranes, Immunofluorescence, Biochemistry, Epithelium, Mice, 0302 clinical medicine, Desmosome, Animal Cells, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Medicine and Health Sciences, Small interfering RNAs, Genetics (clinical), 0303 health sciences, Secretory Pathway, integumentary system, Signal transducing adaptor protein, Desmosomes, Endocytosis, Cell biology, Nucleic acids, medicine.anatomical_structure, Intercellular Junctions, Cell Processes, Cellular Types, Anatomy, Junctional Complexes, Cellular Structures and Organelles, Desmogleins, Research Article, Cell Physiology, lcsh:QH426-470, Biology, Research and Analysis Methods, Desmoglein, Cell Line, 03 medical and health sciences, Ciliogenesis, medicine, Cell Adhesion, Genetics, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cilia, Immunoassays, Non-coding RNA, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Adaptor Proteins, Signal Transducing, Pemphigus vulgaris, Biology and Life Sciences, Membrane Proteins, Epithelial Cells, Cell Biology, medicine.disease, Gene regulation, lcsh:Genetics, Biological Tissue, Membrane protein, Immunologic Techniques, RNA, Gene expression, Epidermis, 030217 neurology & neurosurgery
Abstract: Cilia-related proteins are believed to be involved in a broad range of cellular processes. Retinitis pigmentosa GTPase regulator interacting protein 1-like (RPGRIP1L) is a ciliary protein required for ciliogenesis in many cell types, including epidermal keratinocytes. Here we report that RPGRIP1L is also involved in the maintenance of desmosomal junctions between keratinocytes. Genetically disrupting the Rpgrip1l gene in mice caused intraepidermal blistering, primarily between basal and suprabasal keratinocytes. This blistering phenotype was associated with aberrant expression patterns of desmosomal proteins, impaired desmosome ultrastructure, and compromised cell-cell adhesion in vivo and in vitro. We found that disrupting the RPGRIP1L gene in HaCaT cells, which do not form primary cilia, resulted in mislocalization of desmosomal proteins to the cytoplasm, suggesting a cilia-independent function of RPGRIP1L. Mechanistically, we found that RPGRIP1L regulates the endocytosis of desmogleins such that RPGRIP1L-knockdown not only induced spontaneous desmoglein endocytosis, as determined by AK23 labeling and biotinylation assays, but also exacerbated EGTA- or pemphigus vulgaris IgG-induced desmoglein endocytosis. Accordingly, inhibiting endocytosis with dynasore or sucrose rescued these desmosomal phenotypes. Biotinylation assays on cell surface proteins not only reinforced the role of RPGRIP1L in desmoglein endocytosis, but also suggested that RPGRIP1L may be more broadly involved in endocytosis. Thus, data obtained from this study advanced our understanding of the biological functions of RPGRIP1L by identifying its role in the cellular endocytic pathway., Author summary The desmosome is a type of intercellular junction, essential for cells to adhere to one another. Abnormalities in desmosomes can cause disorders in the hair, skin, and heart, some of which are severe or even fatal. Here, we discovered that RPGRIP1L, a protein known to regulate cilia formation and function, is essential for stabilizing desmosomes of skin keratinocytes. Specifically, suppressing the Rpgrip1l gene in mice or in keratinocytes disrupted the ultrastructure of desmosomes, and compromised cell-cell adhesion in vivo and in vitro. We found that knocking down RPGRIP1L in keratinocytes aberrantly accelerated the internalization of cell membrane desmogleins, key desmosomal cadherins. Inhibiting endocytosis effectively rescued these phenotypes. Biotinylation assays confirmed that desmogleins are likely the primary targets of RPGRIP1L. Interestingly, membrane proteins that are not directly associated with the desmosomes were also found to be internalized in RPGRIP1L-knockdown cells, raising the possibility that RPGRIP1L might regulate endocytosis more broadly. Findings from this study not only identified RPGRIP1L as a regulator of the desmosomes, but also expanded our understanding of cilia-related proteins in the formation of the desmosomal junctions.
Published: 2019

19. Motor axon navigation relies on Fidgetin-like 1–driven microtubule plus end dynamics

Author: Jean-Christophe Larcher, Leticia Peris, Christian Delphin, Stéphanie De Gois, Coralie Fassier, Amélie Fréal, Laïla Gasmi, Daniel Ten Martin, Jamilé Hazan, Christophe Bosc, Philippe Mailly, Corinne Houart, Annie Andrieux, Fatiha Nothias, Céline Revenu, Susanne Bolte, Sylvie Schneider-Maunoury, Monica Tambalo, Développement et dégénérescence des neurones moteurs spinaux = Development and Degeneration of Spinal Motor neurons in the zebrafish (NPS-08), Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Department of Genetics, Universitat de València (UV), Mécanismes d'expression cellulaire des effecteurs humoraux, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie des maladies psychiatriques = Pathophysiology of Psychiatric Disorders (NPS-07), [GIN] Grenoble Institut des Neurosciences, Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Compartimentation et dynamique cellulaires (CDC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Université Pierre et Marie Curie - Paris 6 (UPMC), Organisation Fonctionnelle du Cytosquelette, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR27, Institut des sciences du végétal (ISV), Centre National de la Recherche Scientifique (CNRS), Regionalisation du cerveau des vertébrés - Organogenèse précoce chez la souris et maladies génétiques associées, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), King‘s College London, Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Growth Cones, Biology, Microtubules, Article, Polymerization, 03 medical and health sciences, 0302 clinical medicine, Microtubule, Cell cortex, medicine, Animals, Humans, Protein Isoforms, Axon, Growth cone, Cytoskeleton, Zebrafish, Research Articles, ComputingMilieux_MISCELLANEOUS, Adenosine Triphosphatases, Motor Neurons, Nuclear Proteins, Cell Biology, biology.organism_classification, Axons, Microtubule plus-end, Cell biology, Axon Guidance, 030104 developmental biology, medicine.anatomical_structure, Spinal Cord, Gene Knockdown Techniques, Larva, Axon guidance, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Microtubule-Associated Proteins, 030217 neurology & neurosurgery, Locomotion
Abstract: Fassier et al. identify Fidgetin-like 1 (Fignl1) as a key growth cone (GC)-enriched microtubule (MT)-associated protein in motor circuit wiring. They show that Fignl1 modulates motor GC morphology and steering behavior by down-regulating EB binding at MT plus ends and promoting MT depolymerization beneath the cell cortex., During neural circuit assembly, extrinsic signals are integrated into changes in growth cone (GC) cytoskeleton underlying axon guidance decisions. Microtubules (MTs) were shown to play an instructive role in GC steering. However, the numerous actors required for MT remodeling during axon navigation and their precise mode of action are far from being deciphered. Using loss- and gain-of-function analyses during zebrafish development, we identify in this study the meiotic clade adenosine triphosphatase Fidgetin-like 1 (Fignl1) as a key GC-enriched MT-interacting protein in motor circuit wiring and larval locomotion. We show that Fignl1 controls GC morphology and behavior at intermediate targets by regulating MT plus end dynamics and growth directionality. We further reveal that alternative translation of Fignl1 transcript is a sophisticated mechanism modulating MT dynamics: a full-length isoform regulates MT plus end–tracking protein binding at plus ends, whereas shorter isoforms promote their depolymerization beneath the cell cortex. Our study thus pinpoints Fignl1 as a multifaceted key player in MT remodeling underlying motor circuit connectivity.
Published: 2018

20. Evaluation of off-target and on-target scoring algorithms and integration into the guide RNA selection tool CRISPOR

Author: Jim Kent, Kai Schönig, Jean-Baptiste Renaud, Joffrey Mianné, Helene Eckert, Sylvie Schneider-Maunoury, Lydia Teboul, Jean-Stéphane Joly, Maximilian Haeussler, Alena Shkumatava, Alexis Eschstruth, Jean-Paul Concordet, Santa Cruz Genomics Institute, University of California [Santa Cruz] (UCSC), University of California-University of California, Central Institute of Mental Health, Medical Faculty Mannheim, Génétique et Biologie du Développement, Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire de Biologie du Développement (LBD), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Mary Lyon Centre, MRC, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Morphogénèse du Cerveau des Vertébrés = Morphogenesis of the vertebrate brain (LBD-E10), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure et Instabilité des Génomes (STRING), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), PERIGNON, Alain, University of California [Santa Cruz] (UC Santa Cruz), University of California (UC)-University of California (UC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Mutation rate, Bioinformatics, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.PC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Bioengineering, Biology, Genome, Promoter Regions, arn, 03 medical and health sciences, 0302 clinical medicine, Small Nuclear, Genetic, Genome editing, Information and Computing Sciences, RNA, Small Nuclear, Genetics, False positive paradox, CRISPR, Guide RNA, Kinetoplastida, Promoter Regions, Genetic, Selection (genetic algorithm), Gene Editing, Internet, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Cas9, génome, Research, Human Genome, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Biological Sciences, 030104 developmental biology, RNA, CRISPR-Cas Systems, Algorithm, Guide, Environmental Sciences, algorithme, 030217 neurology & neurosurgery, Algorithms, Software, [SDV.NEU.SC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Biotechnology, RNA, Guide, Kinetoplastida
Abstract: Background The success of the CRISPR/Cas9 genome editing technique depends on the choice of the guide RNA sequence, which is facilitated by various websites. Despite the importance and popularity of these algorithms, it is unclear to which extent their predictions are in agreement with actual measurements. Results We conduct the first independent evaluation of CRISPR/Cas9 predictions. To this end, we collect data from eight SpCas9 off-target studies and compare them with the sites predicted by popular algorithms. We identify problems in one implementation but found that sequence-based off-target predictions are very reliable, identifying most off-targets with mutation rates superior to 0.1 %, while the number of false positives can be largely reduced with a cutoff on the off-target score. We also evaluate on-target efficiency prediction algorithms against available datasets. The correlation between the predictions and the guide activity varied considerably, especially for zebrafish. Together with novel data from our labs, we find that the optimal on-target efficiency prediction model strongly depends on whether the guide RNA is expressed from a U6 promoter or transcribed in vitro. We further demonstrate that the best predictions can significantly reduce the time spent on guide screening. Conclusions To make these guidelines easily accessible to anyone planning a CRISPR genome editing experiment, we built a new website (http://crispor.org) that predicts off-targets and helps select and clone efficient guide sequences for more than 120 genomes using different Cas9 proteins and the eight efficiency scoring systems evaluated here.
Published: 2016

21. Selecting guide RNAs with high on-target and low off-target activity using CRISPOR

Author: Haeussler, M., Schonig, K., Eckert, H., Eschstruth, A., Sylvie Schneider-Maunoury, Shkumatava, A., Kent, J., Joly, J. S., Concordet, J. P., Morphogénèse du Cerveau des Vertébrés = Morphogenesis of the vertebrate brain (LBD-E10), Laboratoire de Biologie du Développement (LBD), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), ProdInra, Migration, University of California [Santa Cruz] (UC Santa Cruz), University of California (UC), Heidelberg University, Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC), USC CNRS jeune équipe Développement, Evolution et Plasticité du Système Nerveux (DEPSN), Institut National de la Recherche Agronomique (INRA), Muséum national d'Histoire naturelle (MNHN), University of California [Santa Cruz] (UCSC), University of California, and Mazalérat, Charlotte
Subjects: [SDV] Life Sciences [q-bio], on-target efficiency, gRNA design, CRISPR design, CRISPR/Cas, [SDV]Life Sciences [q-bio], [SDV.BDD] Life Sciences [q-bio]/Development Biology, gRNA finder, [INFO]Computer Science [cs], [INFO] Computer Science [cs], [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS
Abstract: International audience; no abstract
Published: 2016

22. Initiation of cyp26a1 Expression in the Zebrafish Anterior Neural Plate by a Novel Cis-Acting Element

Author: Aline Stedman, Isabelle Anselme, Chunhong Chen, Daria Onichtchouk, Sylvie Schneider-Maunoury, François Giudicelli, Emmanuelle Havis, HAL UPMC, Gestionnaire, Morphogénèse du Cerveau des Vertébrés = Morphogenesis of the vertebrate brain (LBD-E10), Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and University of Freiburg [Freiburg]
Subjects: 0301 basic medicine, Embryology, Retinoic Acid, Retinoic acid, Gene Expression, lcsh:Medicine, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, Medicine and Health Sciences, Metabolites, lcsh:Science, Zebrafish, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Regulation of gene expression, Genetics, Neural Plate, Multidisciplinary, Fishes, Brain, Animal Models, Cell biology, Chemistry, Osteichthyes, Vertebrates, Physical Sciences, embryonic structures, Anatomy, Sequence Analysis, Neural plate, Research Article, Morphogen, Biology, Research and Analysis Methods, 03 medical and health sciences, CYP26A1, Model Organisms, Sequence Motif Analysis, DNA-binding proteins, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Animals, Gene Regulation, Molecular Biology Techniques, Sequencing Techniques, Enhancer, Molecular Biology, Transcription factor, Embryos, lcsh:R, Organisms, Chemical Compounds, Biology and Life Sciences, Proteins, Zebrafish Proteins, Hindbrain, biology.organism_classification, Regulatory Proteins, Metabolism, 030104 developmental biology, chemistry, lcsh:Q, Acids, 030217 neurology & neurosurgery, Developmental Biology, Transcription Factors
Abstract: International audience; Early patterning of the vertebrate neural plate involves a complex hierarchy of inductive interactions orchestrated by signalling molecules and their antagonists. The morphogen ret-inoic acid, together with the Cyp26 enzymes which degrade it, play a central role in this process. The cyp26a1 gene expressed in the anterior neural plate thus contributes to the fine modulation of the rostrocaudal retinoic acid gradient. Despite this important role of cyp26a1 in early brain formation, the mechanisms that control its expression in the anterior neural plate are totally unknown. Here, we present the isolation of a 310-base-pair DNA element adjacent to cyp26a1 promoter, displaying enhancer activity restricted to the anterior neural plate of the zebrafish gastrula. We show that unlike that of cyp26a1, expression driven by this cyp26a1 anterior neural plate element (cANE) is independent of retinoic acid. Through deletion analysis, we identify a 12-nucleotide motif essential for cANE activity. A consensus bipartite binding site for SoxB:Oct transcription factors overlaps with this motif. Mutational analysis suggests that SoxB binding is essential for its activity. We discuss the contribution of this study to the elucidation of the regulatory hierarchy involved in early neural plate patterning.
Published: 2016

23. C-Nap1 mutation affects centriole cohesion and is associated with a Seckel-like syndrome in cattle

Author: Sabrina Rodriguez, Erich A. Nigg, Didier Boichard, Joyce El Hokayem, Christine Vesque, Sophie Halliez, Raphaël Guatteo, Geraldine Toutirais, Sébastien Fritz, Sandrine Floriot, Amandine Duchesne, Anthi Karaiskou, Maud Bertaud, Joëlle Sobczak-Thépot, Mohammed Moudjou, Alexandre Vasilescu, Sylvie Schneider-Maunoury, Luc Manciaux, Nora Cesbron, Sarah Barbey, Laurent Schibler, Valérie Cormier-Daire, André Eggen, Mathieu Gautier, Florence Bourgain-Guglielmetti, ProdInra, Archive Ouverte, Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), ERL 1156, Institut National de la Santé et de la Recherche Médicale (INSERM), Plate-forme SIGENAE/Génétique Cellulaire, Institut National de la Recherche Agronomique (INRA), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Biologie pour la Gestion des Populations (UMR CBGP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Domaine Expérimental du Pin (DEP), Département R&D, Allice, Laboratoire d'Analyse Génétique pour les Espèces Animales (LABOGENA), Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department Biozentrum, University of Basel (Unibas), Centre Européen d'Informatique et d'Automation du Doubs et du Territoire de Belfort (CEIA), Biologie, Epidémiologie et analyse de risque en Santé Animale (BIOEPAR), Institut National de la Recherche Agronomique (INRA)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Microscopie Electronique [IBPS] (IBPS-ME), Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Contrat privé Apisgene, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Domaine expérimental animal du Pin (SEA), Unité de recherche Virologie et Immunologie Moléculaires (VIM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UMR 1300 Biologie, Epidémiologie et Analyse du Risque, Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Biologie, Epidémiologie et Analyse du Risque (BioEpAR)-Santé animale (S.A.), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Génétique Animale et Biologie Intégrative ( GABI ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, Laboratoire de Biologie du Développement ( LBD ), Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut National de la Santé et de la Recherche Médicale, Institut National de la Recherche Agronomique ( INRA ), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Biologie pour la Gestion des Populations ( CBGP ), Centre de Coopération Internationale en Recherche Agronomique pour le Développement ( CIRAD ) -Centre international d'études supérieures en sciences agronomiques ( Montpellier SupAgro ) -Institut national de la recherche agronomique [Montpellier] ( INRA Montpellier ) -Université de Montpellier ( UM ) -Institut de Recherche pour le Développement ( IRD [France-Sud] ) -Institut national d’études supérieures agronomiques de Montpellier ( Montpellier SupAgro ), Domaine expérimental animal du Pin ( SEA ), Laboratoire d'Analyse Génétique pour les Espèces Animales ( LABOGENA ), Unité de recherche Virologie et Immunologie Moléculaires ( VIM ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), University of Basel ( Unibas ), Centre Européen d'Informatique et d'Automation du Doubs et du Territoire de Belfort ( CEIA ), Institut National de la Recherche Agronomique ( INRA ) -Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique ( ONIRIS ) -Biologie, Epidémiologie et Analyse du Risque ( BioEpAR ) -Santé animale ( S.A. ), Biologie, Epidémiologie et analyse de risque en Santé Animale ( BIOEPAR ), Microscopie Electronique [IBPS] ( IBPS-ME ), Institut de Biologie Paris Seine ( IBPS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)
Subjects: Microcephaly, bovin, Centriole, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Cattle Diseases, Cell Cycle Proteins, Biology, gène CEP250, protéine C-Nap1, anomalie génétique, syndrome de Seckel, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Muscular Diseases, Cell Movement, medicine, Morphogenesis, Animals, 030304 developmental biology, Centrioles, Genetics, Hypopigmentation, 0303 health sciences, Mutation, Multidisciplinary, [ SDV ] Life Sciences [q-bio], Mitotic spindle organization, General Chemistry, Syndrome, medicine.disease, Cilium assembly, Hypoplasia, CEP250, [SDV] Life Sciences [q-bio], Centrosome, Cattle, 030217 neurology & neurosurgery
Abstract: Caprine-like Generalized Hypoplasia Syndrome (SHGC) is an autosomal-recessive disorder in Montbéliarde cattle. Affected animals present a wide range of clinical features that include the following: delayed development with low birth weight, hind limb muscular hypoplasia, caprine-like thin head and partial coat depigmentation. Here we show that SHGC is caused by a truncating mutation in the CEP250 gene that encodes the centrosomal protein C-Nap1. This mutation results in centrosome splitting, which neither affects centriole ultrastructure and duplication in dividing cells nor centriole function in cilium assembly and mitotic spindle organization. Loss of C-Nap1-mediated centriole cohesion leads to an altered cell migration phenotype. This discovery extends the range of loci that constitute the spectrum of autosomal primary recessive microcephaly (MCPH) and Seckel-like syndromes., SHGC syndrome affects cattle and has clinical features similar to human Seckel syndrome. Here Floriot et al. identify the causative mutation in the centrosomal protein C-Nap1 that affects centriole cohesion and cell migration, extending the range of loci involved in human Seckel-like syndromes.
Published: 2015

24. Mechanisms of cranial placode assembly

Author: Marie Anne Breau, Sylvie Schneider-Maunoury, Morphogénèse du Cerveau des Vertébrés = Morphogenesis of the vertebrate brain (LBD-E10), Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Fondation pour la Recherche Biomedicale
Subjects: Embryology, coalescence, sensory organ, cell migration, Vertebrate, Gene Expression Regulation, Developmental, Nerve Tissue Proteins, Anatomy, Biology, Cell fate determination, Embryonic stem cell, Nervous System, sorting-out, Clonal Evolution, biology.animal, Ectoderm, Animals, Humans, cranial placode, Neuroscience, Neural plate, Head, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Developmental Biology
Abstract: International audience; Cranial placodes are transient ectodermal structures contributing to the paired sensory organs and ganglia of the vertebrate head. Placode progenitors are initially spread and intermixed within a continuous embryonic territory surrounding the anterior neural plate, the so-called pan-placodal region, which progressively breaks into distinct and compact placodal structures. The mechanisms driving the formation of these discrete placodes from the initial scattered distribution of their progenitors are poorly understood, and the implication of cell fate changes, local sorting out or massive cell movements is still a matter of debate. Here, we discuss different models that could account for placode assembly and review recent studies unraveling novel cellular and molecular aspects of this key event in the construction of the vertebrate head.
Published: 2014

25. Dishevelled stablisation at the cilium by RPGRIP1L is essential for planar cell polarity

Author: Sylvie Schneider-Maunoury, Christine Vesque, Hm Gaudé, Mireille Montcouquiol, Isabelle Anselme, Flora Silbermann, Margot Leroux-Berger, Sophie Saunier, Alexia Mahuzier, BMC, Ed., Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Physiopathologie du système nerveux central - Institut François Magendie, and Université Bordeaux Segalen - Bordeaux 2-IFR8-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: animal structures, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, 0302 clinical medicine, GLI3, Basal body, lcsh:QH573-671, Zebrafish, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Floor plate, chemistry.chemical_classification, 0303 health sciences, lcsh:Cytology, Cilium, Ciliary transition zone, Cell Biology, biology.organism_classification, Dishevelled, Cell biology, [SDV.TOX] Life Sciences [q-bio]/Toxicology, chemistry, RPGRIP1L, [SDV.TOX]Life Sciences [q-bio]/Toxicology, embryonic structures, Oral Presentation, 030217 neurology & neurosurgery
Abstract: Cilia are involved in planar polarity in different systems but the mechanisms by which they influence the polarization process are unclear [1]. In order to clarify this issue, we investigated the function of the ciliary gene Rpgrip1l (Ftm/NPHP8/MKS5) in the mammalian cochlear sensory epithelium and in the zebrafish floor plate. We and others have previously shown that mutations in the human RPGRIP1L gene cause Meckel and Joubert type B syndromes [2]. The Rpgrip1l protein is localised at the ciliary transition zone and is required for transduction of the Hh/ Gli pathway [3]. Our recent work has shown that Rpgrip1l patterns the telencephalon via the regulation of Gli3 proteolytic cleavage [4]. Here we show that in both the mammalian cochlear sensory epithelium and the zebrafish floor plate, Rpgrip1l is required for correct positioning of the basal body along the planar polarity axis. Our results strongly suggest that Rpgrip1l is essential for stabilizing the adaptor protein dishevelled at the basal body and/or cilium. Finally, we demonstrate that, in the zebrafish floor plate, the function of Rpgrip1l in basal body positioning is mediated by dishevelled. We propose that Rpgrip1l participates in a protein complex required for stabilizing dishevelled at the cilium, and that this stabilization is essential for asymmetric localization of the basal body along the planar polarity axis.
Published: 2012

26. Dishevelled stabilization by the ciliopathy protein Rpgrip1l is essential for planar cell polarity

Author: Isabelle Anselme, Mireille Montcouquiol, Sophie Saunier, Alexia Mahuzier, Christine Vesque, Sylvie Schneider-Maunoury, Helori-Mael Gaudé, Jerome Ezan, Flora Silbermann, Valentina Grampa, Delphine Delacour, Margot Leroux-Berger, Regionalisation du cerveau des vertébrés - Organogenèse précoce chez la souris et maladies génétiques associées, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Néphropathies héréditaires et rein en développement (UMR_S 983), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie du système nerveux central - Institut François Magendie, Université Bordeaux Segalen - Bordeaux 2-IFR8-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the Université Pierre et Marie Curie, the Agence Nationale de la Recherche grant R07089KS, Association pour la Recherche sur le Cancer 4951XA0731F and SFI20101201851, the Fondation pour la Recherche Médicale ('Equipe FRM' grant DEQ20071210558, the Association pour l'Utilization du Rein Artificiel (AURA), the Société de Néphrologie, the Association pour l'Information et la Recherche sur les maladies Rénales Génétiques (AIRG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: animal structures, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Article, Cell Line, 03 medical and health sciences, Mice, 0302 clinical medicine, stomatognathic system, Cell polarity, medicine, Basal body, Animals, Cilia, Cytoskeleton, Zebrafish, Research Articles, 030304 developmental biology, Floor plate, chemistry.chemical_classification, 0303 health sciences, biology, Cilium, fungi, Cell Polarity, Proteins, Cell Biology, Zebrafish Proteins, medicine.disease, biology.organism_classification, Dishevelled, Cell biology, Cochlea, Mice, Inbred C57BL, Ciliopathy, Cytoskeletal Proteins, chemistry, embryonic structures, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Rpgrip1l is required for planar localization of the basal body and acts within a ciliopathy protein complex by stabilizing dishevelled., Cilia are at the core of planar polarity cellular events in many systems. However, the molecular mechanisms by which they influence the polarization process are unclear. Here, we identify the function of the ciliopathy protein Rpgrip1l in planar polarity. In the mouse cochlea and in the zebrafish floor plate, Rpgrip1l was required for positioning the basal body along the planar polarity axis. Rpgrip1l was also essential for stabilizing dishevelled at the cilium base in the zebrafish floor plate and in mammalian renal cells. In rescue experiments, we showed that in the zebrafish floor plate the function of Rpgrip1l in planar polarity was mediated by dishevelled stabilization. In cultured cells, Rpgrip1l participated in a complex with inversin and nephrocystin-4, two ciliopathy proteins known to target dishevelled to the proteasome, and, in this complex, Rpgrip1l prevented dishevelled degradation. We thus uncover a ciliopathy protein complex that finely tunes dishevelled levels, thereby modulating planar cell polarity processes.
Published: 2012

27. Primary cilia control telencephalic patterning and morphogenesis via Gli3 proteolytic processing

Author: Mariame Neti, Sylvie Schneider-Maunoury, Christoph Gerhardt, Christine Laclef, Laurianne Besse, Ulrich Rüther, Isabelle Anselme, Morphogénèse du Cerveau des Vertébrés = Morphogenesis of the vertebrate brain (LBD-E10), Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Telencephalon, [SDV]Life Sciences [q-bio], Mice, 0302 clinical medicine, Pregnancy, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Morphogenesis, [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS, Genetics, Mice, Knockout, 0303 health sciences, Cerebrum, Cilium, Cell Differentiation, Olfactory Bulb, Cell biology, medicine.anatomical_structure, RPGRIP1L, Female, Sensory Receptor Cells, Kruppel-Like Transcription Factors, Nerve Tissue Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, Zinc Finger Protein Gli3, medicine, Animals, Humans, Cilia, Molecular Biology, Process (anatomy), 030304 developmental biology, Adaptor Proteins, Signal Transducing, Body Patterning, DNA Primers, Base Sequence, [SDV.BDD.MOR]Life Sciences [q-bio]/Development Biology/Morphogenesis, medicine.disease, Mice, Mutant Strains, Olfactory bulb, Mice, Inbred C57BL, Ciliopathy, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Mutation, Microscopy, Electron, Scanning, Mutant Proteins, Brain morphogenesis, Protein Processing, Post-Translational, 030217 neurology & neurosurgery, Developmental Biology
Abstract: Primary cilia have essential functions in vertebrate development and signaling. However, little is known about cilia function in brain morphogenesis, a process that is severely affected in human ciliopathies. Here, we study telencephalic morphogenesis in a mouse mutant for the ciliopathy gene Ftm (Rpgrip1l). We show that the olfactory bulbs are present in an ectopic location in the telencephalon of Ftm−/− fetuses and do not display morphological outgrowth at the end of gestation. Investigating the developmental origin of this defect, we have established that E12.5 Ftm−/− telencephalic neuroepithelial cells lack primary cilia. Moreover, in the anterior telencephalon, the subpallium is expanded at the expense of the pallium, a phenotype reminiscent of Gli3 mutants. This phenotype indeed correlates with a decreased production of the short form of the Gli3 protein. Introduction of a Gli3 mutant allele encoding the short form of Gli3 into Ftm mutants rescues both telencephalic patterning and olfactory bulb morphogenesis, despite the persistence of cilia defects. Together, our results show that olfactory bulb morphogenesis depends on primary cilia and that the essential role of cilia in this process is to produce processed Gli3R required for developmental patterning. Our analysis thus provides the first in vivo demonstration that primary cilia control a developmental process via production of the short, repressor form of Gli3. Moreover, our findings shed light on the developmental origin of olfactory bulb agenesis and of other brain morphogenetic defects found in human diseases affecting the primary cilium.
Published: 2011

28. Rescue of corpus callosum agenesis in two ciliary mutants by the short repressor isoform of Gli3

Author: Christine Laclef, Sylvie Schneider-Maunoury, Isabelle Anselme, Bénédicte Durand, Laurianne Besse, Dominique Baas, Martin Catala, and M Paschaki
Subjects: Genetics, Corpus Callosum Agenesis, Cilium, Ciliary transition zone, Cell Biology, Biology, medicine.disease, Cell biology, Neuroepithelial cell, Ciliogenesis, GLI3, Forebrain, Poster Presentation, medicine, Agenesis of the corpus callosum
Abstract: Agenesis of the Corpus callosum (AgCC) is a frequent brain disorder found in over 50 human congenital syndromes including ciliopathies. Here, we report a severe AgCC in Ftm/Rpgrip1l knock-out mice, which provide a valuable model for Meckel-Gruber syndrome. Ftm encodes a protein of the ciliary transition zone, which is essential for ciliogenesis in some, but not all cell types in mice, including neuroepithelial cells in the developing forebrain. We show that AgCC in Ftm-/- fetuses results from a mislocalization of guidepost cells in the dorsomedial telencephalon and not from a reduction of callosal neurons in the cortex. This abnormal distribution of the guideposts primarily results from patterning defects in the medial telencephalon, which relies on Gli3 processing defects. These patterning defects, mispositioning of dorsomedial guideposts and AgCC can all be rescued by reintroducing Gli3R in Ftm-/- embryos, provided by the Gli3D699 allele, which produces only the short repressor isoform of Gli3. This rescue of AgCC of Ftm-/- mutants by one allele of Gli3D699 confirms and completes our knowledge on the pre-eminent role of Gli3 in CC formation. Furthermore, Gli3D699 also rescue AgCC in Rfx3-/- mutant, another ciliary mutant deficient for a transcription factor controlling several ciliary genes. Rescuing the CC formation in two independent ciliary mutants by a single molecule, namely Gli3R, highlight the crucial role of primary cilia in maintaining the proper level of Gli3R required for CC morphogenesis. These data demonstrate that Gli3 processing is the major outcome of primary cilia function in CC formation.
Published: 2015

29. Function of the Ciliopathy gene RPGRIP1L in cortical neurogenesis

Author: M Catala, Guillaume Pézeron, Isabelle Anselme, Christine Laclef, and Sylvie Schneider-Maunoury
Subjects: Cilium, Neurogenesis, Cell, Cell Biology, Computational biology, Biology, medicine.disease, Cell biology, Ciliopathy, medicine.anatomical_structure, RPGRIP1L, Poster Presentation, medicine, Progenitor cell, Developmental biology, Progenitor
Abstract: Methods We use a mouse knock-out mutant line, Ftm, to identify the role of Rpgrip1l in cortical neurogenesis. Two distinct pools of progenitors undergo extensive cell divisions to form cortical projection neurons. Radial Glial Cells (RGCs) divide either symmetrically to expand the progenitor pool or asymmetrically to self-renew and produce an Intermediate Progenitor Cell (IPC), which divides once to form two neurons. The balance between differentiation and proliferation is coordinated by multiple signalling pathways, among which several depend on the primary cilium.
Published: 2015

30. The transmembrane semaphorin Sema6A controls cerebellar granule cell migration

Author: Kevin J. Mitchell, Cécile Haumaitre, Géraldine Kerjan, Hajime Fujisawa, Sylvie Schneider-Maunoury, Alain Chédotal, Jackie Dolan, Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Smurfit Institute of Genetics, Trinity College Dublin, Laboratoire de Biologie du Développement (LBD), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The 21st Century Center of Excellence Program, Division of Biological Science, Nagoya University Graduate School of Science, A.C. is supported by the Fondation pour la Recherche sur le Cerveau (FRC), the Schlumberger Foundation and the Association pour la Recherche sur le Cancer (ARC). K.J.M is a Science Foundation Ireland (SFI) Investigator. This work was supported by SFI grant 01/F.1/B006 to K.J.M, and grants from the 21st Century COE Program, and from the Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology Agency (JST) to H.F., Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cerebellum, Time Factors, granule cell migration, Phalloidine, cerebellum development, Semaphorins, Mice, Cell Movement, Tubulin, Cricetinae, granule cell layer, Basic Helix-Loop-Helix Transcription Factors, Cells, Cultured, In Situ Hybridization, Neurons, Sema6A, Microscopy, Video, General Neuroscience, Granule (cell biology), Cell Polarity, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Cell Differentiation, Dextrans, Immunohistochemistry, medicine.anatomical_structure, CXCL3, transmembrane semaphorin protein, developing axons, Neurite, Cell Adhesion Molecules, Neuronal, Blotting, Western, Green Fluorescent Proteins, Biotin, Mice, Transgenic, Biology, Cricetulus, Semaphorin, Glial Fibrillary Acidic Protein, medicine, Contactin 2, Animals, Cell Proliferation, Analysis of Variance, Calcium-Binding Proteins, ACM, Granule cell, Oligodendrocyte, Mice, Inbred C57BL, Animals, Newborn, Bromodeoxyuridine, nervous system, Calcium-Calmodulin-Dependent Protein Kinases, Vesicular Glutamate Transport Protein 2, Axon guidance, Neuroscience, Calcium-Calmodulin-Dependent Protein Kinase Type 4
Abstract: The transmembrane semaphorin protein Sema6A is broadly expressed in the developing nervous system. Sema6A repels several classes of developing axons in vitro and contributes to thalamocortical axon guidance in vivo. Here we show that during cerebellum development, Sema6A is selectively expressed by postmitotic granule cells during their tangential migration in the deep external granule cell layer, but not during their radial migration. In Sema6A-deficient mice, many granule cells remain ectopic in the molecular layer where they differentiate and are contacted by mossy fibers. The analysis of ectopic granule cell morphology in Sema6a-/- mice, and of granule cell migration and neurite outgrowth in cerebellar explants, suggests that Sema6A controls the initiation of granule cell radial migration, probably through a modulation of nuclear and/or soma translocation. Finally, the analysis of mouse chimeras suggests that this function of Sema6A is primarily non-cell-autonomous.
Published: 2005

31. Multiple pituitary and ovarian defects in Krox-24 (NGFI-A, Egr-1)-targeted mice

Author: Topilko, P., Sylvie Schneider-Maunoury, Levi, G., Trembleau, A., Gourdji, D., Driancourt, M. A., Rao, C. V., Charnay, P., Unité de recherche Physiologie de la reproduction des mammifères domestiques, Nouzilly, Institut National de la Recherche Agronomique (INRA), and ProdInra, Migration
Subjects: [SDV] Life Sciences [q-bio], LH, [SDV]Life Sciences [q-bio], FEMELLE MALE CELLULE SOMATOTROPE, [INFO]Computer Science [cs], [INFO] Computer Science [cs], GENE KROX-24, ComputingMilieux_MISCELLANEOUS, GH
Abstract: International audience
Published: 1997

32. Multi-fonctional role of the Krox-20 regulatory gene: from specification of positional information to cell differentiation

Author: Tania Seitanidou, Sylvie Schneider-Maunoury, Poitr Topilko, Giovanni Levi, Monique Frain, Paula Murphy, Christine Vesque, Patrick Charnay, Génétique moléculaire du développement, Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-IFR36-Institut National de la Santé et de la Recherche Médicale (INSERM), Harwood Academic Publishers, and FRAIN, Monique
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 1996

33. Cloning of vertebrate Protogenin (Prtg) and comparative expression analysis during axis elongation.

Author: Christine Vesque, Isabelle Anselme, Elisabeth Couvé, Patrick Charnay, and Sylvie Schneider‐Maunoury
Published: 2006

34. Role of the ciliopathy gene Ftm/Rpgrip1l and primary cilia in forebrain patterning and morphogenesis

Author: Andreu Cervera, Abraham, Laboratoire de Biologie du Développement [Paris] (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université, and Sylvie Schneider-Maunoury
Subjects: Ciliopathy, Hypothalamus, Cils primaires, Ciliopathie, Primary cilia, Diencéphale, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Morphogenesis, Forebrain, Morphogénèse, Cerveau antérieur, Diencephalon, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Holoprosencéphale, Hedgehog, Gli
Abstract: Primary cilia are essential for central nervous system development. In the mouse, they play a critical role in patterning the spinal cord and telencephalon via the regulation of Hedgehog/Gli signaling. However, despite the frequent disruption of this signaling pathway in human forebrain malformations, the role of primary cilia in forebrain morphogenesis has been little investigated outside the telencephalon. Here we studied development of the diencephalon, hypothalamus and eyes in mutant mice in which the Ftm/Rgprip1l ciliopathy gene is disrupted. At the end of gestation, Ftm-/- fetuses displayed anophthalmia, a reduction of the ventral hypothalamus and a disorganization of diencephalic nuclei and axonal tracts. In Ftm-/- embryos, we found that the ventral forebrain structures and the rostral thalamus were missing. Optic vesicles formed but lacked the optic cups. We analyzed the molecular causes of these defects. In Ftm-/- embryos, Sonic hedgehog (Shh) expression was lost in the ventral forebrain but maintained in the zona limitans intrathalamica (ZLI), the mid-diencephalic organizer. In the diencephalon, Gli activity was dampened in regions adjacent to the Shh-expressing ZLI but displayed a higher Hh-independent ground level in the other regions. Our data uncover a complex role of cilia in development of the diencephalon, hypothalamus and eyes via the region-specific control of the ratio of activator and repressor forms of the Gli transcription factors. They call for a closer examination of forebrain defects in severe ciliopathies and for a search for ciliopathy genes as modifiers in other human conditions with forebrain defects.; Les cils primaires sont essentiels au développement du système nerveux central. Chez la souris, ils jouent un rôle essentiel dans l’organisation de la moelle épinière et du télencéphale via la régulation de la signalisation Hedgehog/Gli. Cependant, malgré la perturbation fréquente de cette voie de signalisation dans les malformations du cerveau antérieur chez l'homme, le rôle des cils primaires dans la morphogenèse du cerveau antérieur a été peu étudié en dehors du télencéphale. Pendant mon doctorat, j’ai étudié le développement du diencéphale, de l’hypothalamus et des yeux chez des souris mutantes pour le gène de ciliopathie Ftm/Rgprip1l. En fin de gestation, les fœtus Ftm-/- présentent une anophtalmie, une réduction de l'hypothalamus ventral et une désorganisation du diencéphale. Chez les embryons Ftm-/-, l'expression de Sonic hedgehog (Shh) est perdue dans le cerveau antérieur ventral, mais maintenue dans la zona limitans intrathalamica (ZLI), l'organisateur diencéphalique. Dans le diencéphale, l'activité de Gli est atténuée dans les régions adjacentes à la ZLI, mais montre un niveau de base plus élevé dans les autres régions. Nos données révèlent un rôle complexe des cils dans le développement du diencéphale, de l'hypothalamus et des yeux via le contrôle régional du ratio entre les formes activatrices et répressives des facteurs de transcription Gli. Ils sont en faveur d’un examen plus approfondi des anomalies du cerveau antérieur dans les ciliopathies sévères et de la recherche de gènes de ciliopathie comme modificateurs dans d'autres maladies humaines présentant des anomalies du cerveau antérieur.
Published: 2018

35. Rôle du gène de ciliopathie Ftm/Rpgrip1l et des cils primaires dans la régionalisation et la morphogenèse du cerveau antérieur

Author: Andreu Cervera, Abraham, Laboratoire de Biologie du Développement [Paris] (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université, and Sylvie Schneider-Maunoury
Subjects: Ciliopathy, Hypothalamus, Cils primaires, Ciliopathie, Primary cilia, Diencéphale, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Morphogenesis, Forebrain, Morphogénèse, Cerveau antérieur, Diencephalon, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Holoprosencéphale, Hedgehog, Gli
Abstract: Primary cilia are essential for central nervous system development. In the mouse, they play a critical role in patterning the spinal cord and telencephalon via the regulation of Hedgehog/Gli signaling. However, despite the frequent disruption of this signaling pathway in human forebrain malformations, the role of primary cilia in forebrain morphogenesis has been little investigated outside the telencephalon. Here we studied development of the diencephalon, hypothalamus and eyes in mutant mice in which the Ftm/Rgprip1l ciliopathy gene is disrupted. At the end of gestation, Ftm-/- fetuses displayed anophthalmia, a reduction of the ventral hypothalamus and a disorganization of diencephalic nuclei and axonal tracts. In Ftm-/- embryos, we found that the ventral forebrain structures and the rostral thalamus were missing. Optic vesicles formed but lacked the optic cups. We analyzed the molecular causes of these defects. In Ftm-/- embryos, Sonic hedgehog (Shh) expression was lost in the ventral forebrain but maintained in the zona limitans intrathalamica (ZLI), the mid-diencephalic organizer. In the diencephalon, Gli activity was dampened in regions adjacent to the Shh-expressing ZLI but displayed a higher Hh-independent ground level in the other regions. Our data uncover a complex role of cilia in development of the diencephalon, hypothalamus and eyes via the region-specific control of the ratio of activator and repressor forms of the Gli transcription factors. They call for a closer examination of forebrain defects in severe ciliopathies and for a search for ciliopathy genes as modifiers in other human conditions with forebrain defects.; Les cils primaires sont essentiels au développement du système nerveux central. Chez la souris, ils jouent un rôle essentiel dans l’organisation de la moelle épinière et du télencéphale via la régulation de la signalisation Hedgehog/Gli. Cependant, malgré la perturbation fréquente de cette voie de signalisation dans les malformations du cerveau antérieur chez l'homme, le rôle des cils primaires dans la morphogenèse du cerveau antérieur a été peu étudié en dehors du télencéphale. Pendant mon doctorat, j’ai étudié le développement du diencéphale, de l’hypothalamus et des yeux chez des souris mutantes pour le gène de ciliopathie Ftm/Rgprip1l. En fin de gestation, les fœtus Ftm-/- présentent une anophtalmie, une réduction de l'hypothalamus ventral et une désorganisation du diencéphale. Chez les embryons Ftm-/-, l'expression de Sonic hedgehog (Shh) est perdue dans le cerveau antérieur ventral, mais maintenue dans la zona limitans intrathalamica (ZLI), l'organisateur diencéphalique. Dans le diencéphale, l'activité de Gli est atténuée dans les régions adjacentes à la ZLI, mais montre un niveau de base plus élevé dans les autres régions. Nos données révèlent un rôle complexe des cils dans le développement du diencéphale, de l'hypothalamus et des yeux via le contrôle régional du ratio entre les formes activatrices et répressives des facteurs de transcription Gli. Ils sont en faveur d’un examen plus approfondi des anomalies du cerveau antérieur dans les ciliopathies sévères et de la recherche de gènes de ciliopathie comme modificateurs dans d'autres maladies humaines présentant des anomalies du cerveau antérieur.
Published: 2018

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35 results on '"Sylvie Schneider-Maunoury"'

1. Astrogliosis and neuroinflammation underlie scoliosis upon cilia dysfunction

2. Centriole Translational Planar Polarity in Monociliated Epithelia

3. A multiscale mathematical model of cell dynamics during neurogenesis in the mouse cerebral cortex

4. Cilia, ciliopathies and hedgehog-related forebrain developmental disorders

5. A transient role of the ciliary gene Inpp5e in controlling direct versus indirect neurogenesis in cortical development

6. MKS-NPHP module proteins control ciliary shedding at the transition zone.

7. RPGRIP1L is required for stabilizing epidermal keratinocyte adhesion through regulating desmoglein endocytosis.

8. An in vivo translation-reporter system for the study of protein synthesis in zebrafish embryos

9. Initiation of cyp26a1 Expression in the Zebrafish Anterior Neural Plate by a Novel Cis-Acting Element.

10. Whole embryo chromatin immunoprecipitation protocol for the in vivo study of zebrafish development

11. Functional analysis of the NUP98-CCDC28A fusion protein

12. Rpgrip1l controls ciliary gating by ensuring the proper amount of Cep290 at the vertebrate transition zone

13. Cilia, ciliopathies and hedgehog-related forebrain developmental disorders

14. Primary cilium-dependent cAMP/PKA signaling at the centrosome regulates neuronal migration

15. A transient role of the ciliary gene Inpp5e in controlling direct versus indirect neurogenesis in cortical development

16. A transient role of primary cilia in controlling direct versus indirect neurogenesis in the developing cerebral cortex

17. Rpgrip1l controls ciliary gating by ensuring the proper amount of Cep290 at the vertebrate transition zone

18. RPGRIP1L is required for stabilizing epidermal keratinocyte adhesion through regulating desmoglein endocytosis

19. Motor axon navigation relies on Fidgetin-like 1–driven microtubule plus end dynamics

20. Evaluation of off-target and on-target scoring algorithms and integration into the guide RNA selection tool CRISPOR

21. Selecting guide RNAs with high on-target and low off-target activity using CRISPOR

22. Initiation of cyp26a1 Expression in the Zebrafish Anterior Neural Plate by a Novel Cis-Acting Element

23. C-Nap1 mutation affects centriole cohesion and is associated with a Seckel-like syndrome in cattle

24. Mechanisms of cranial placode assembly

25. Dishevelled stablisation at the cilium by RPGRIP1L is essential for planar cell polarity

26. Dishevelled stabilization by the ciliopathy protein Rpgrip1l is essential for planar cell polarity

27. Primary cilia control telencephalic patterning and morphogenesis via Gli3 proteolytic processing

28. Rescue of corpus callosum agenesis in two ciliary mutants by the short repressor isoform of Gli3

29. Function of the Ciliopathy gene RPGRIP1L in cortical neurogenesis

30. The transmembrane semaphorin Sema6A controls cerebellar granule cell migration

31. Multiple pituitary and ovarian defects in Krox-24 (NGFI-A, Egr-1)-targeted mice

32. Multi-fonctional role of the Krox-20 regulatory gene: from specification of positional information to cell differentiation

33. Cloning of vertebrate Protogenin (Prtg) and comparative expression analysis during axis elongation.

34. Role of the ciliopathy gene Ftm/Rpgrip1l and primary cilia in forebrain patterning and morphogenesis

35. Rôle du gène de ciliopathie Ftm/Rpgrip1l et des cils primaires dans la régionalisation et la morphogenèse du cerveau antérieur

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35 results on '"Sylvie Schneider-Maunoury"'

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