37 results on '"Nguyen, Laurent"'
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2. Neuron-glia crosstalk shapes brain morphogenesis.
- Author
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Nguyen L
- Subjects
- Brain, Neurogenesis, Neuroglia, Neurons
- Published
- 2022
- Full Text
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3. Coordination between Transport and Local Translation in Neurons.
- Author
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Broix L, Turchetto S, and Nguyen L
- Subjects
- Animals, Humans, Microtubules metabolism, Models, Neurological, Organelles metabolism, Axons metabolism, Neurons metabolism, RNA Transport, RNA, Messenger metabolism
- Abstract
The axonal microtubules (MTs) support long-distance transport of cargoes that are dispatched to distinct cellular subcompartments. Among them, mRNAs are directly transported in membraneless ribonucleoprotein (RNP) granules that, together with ribosomes, can also hitchhike on fast-moving membrane-bound organelles for accurate transport along MTs. These organelles serve as platforms for mRNA translation, thus generating axonal foci of newly synthesized proteins. Local translation along axons not only supports MT network integrity but also modulates the processivity and function of molecular motors to allow proper trafficking of cargoes along MTs. Thus, identifying the mechanisms that coordinate axonal transport with local protein synthesis will shed new light on the processes underlying axon development and maintenance, whose deregulation often contribute to neurological disorders., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
- Full Text
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4. Cerebral Cortical Circuitry Formation Requires Functional Glycine Receptors.
- Author
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Morelli G, Avila A, Ravanidis S, Aourz N, Neve RL, Smolders I, Harvey RJ, Rigo JM, Nguyen L, and Brône B
- Subjects
- Animals, Cerebral Cortex cytology, Disease Models, Animal, Immunohistochemistry, Male, Membrane Potentials physiology, Mice, Inbred C57BL, Mice, Knockout, Neural Pathways cytology, Neural Pathways embryology, Neural Pathways metabolism, Neurons cytology, Patch-Clamp Techniques, Pentylenetetrazole, Receptors, Glycine genetics, Seizures metabolism, Tissue Culture Techniques, Cerebral Cortex embryology, Cerebral Cortex metabolism, Neurons metabolism, Receptors, Glycine metabolism
- Abstract
The development of the cerebral cortex is a complex process that requires the generation, migration, and differentiation of neurons. Interfering with any of these steps can impair the establishment of connectivity and, hence, function of the adult brain. Neurotransmitter receptors have emerged as critical players to regulate these biological steps during brain maturation. Among them, α2 subunit-containing glycine receptors (GlyRs) regulate cortical neurogenesis and the present work demonstrates the long-term consequences of their genetic disruption on neuronal connectivity in the postnatal cerebral cortex. Our data indicate that somatosensory cortical neurons of Glra2 knockout mice (Glra2KO) have more dendritic branches with an overall increase in total spine number. These morphological defects correlate with a disruption of the excitation/inhibition balance, thereby increasing network excitability and enhancing susceptibility to epileptic seizures after pentylenetetrazol tail infusion. Taken together, our findings show that the loss of embryonic GlyRα2 ultimately impairs the formation of cortical circuits in the mature brain., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2017
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5. Neural Stem Cells to Cerebral Cortex: Emerging Mechanisms Regulating Progenitor Behavior and Productivity.
- Author
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Dwyer ND, Chen B, Chou SJ, Hippenmeyer S, Nguyen L, and Ghashghaei HT
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- Animals, Cell Differentiation physiology, Cell Proliferation physiology, Humans, Neuronal Plasticity physiology, Cerebral Cortex cytology, Cerebral Cortex physiology, Cytokinesis physiology, Neurogenesis physiology, Neurons cytology, Neurons physiology
- Abstract
This review accompanies a 2016 SFN mini-symposium presenting examples of current studies that address a central question: How do neural stem cells (NSCs) divide in different ways to produce heterogeneous daughter types at the right time and in proper numbers to build a cerebral cortex with the appropriate size and structure? We will focus on four aspects of corticogenesis: cytokinesis events that follow apical mitoses of NSCs; coordinating abscission with delamination from the apical membrane; timing of neurogenesis and its indirect regulation through emergence of intermediate progenitors; and capacity of single NSCs to generate the correct number and laminar fate of cortical neurons. Defects in these mechanisms can cause microcephaly and other brain malformations, and understanding them is critical to designing diagnostic tools and preventive and corrective therapies., (Copyright © 2016 the authors 0270-6474/16/3611394-08$15.00/0.)
- Published
- 2016
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6. Real-time Recordings of Migrating Cortical Neurons from GFP and Cre Recombinase Expressing Mice.
- Author
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Tielens S, Godin JD, and Nguyen L
- Subjects
- Animals, Cerebral Cortex cytology, Green Fluorescent Proteins metabolism, Integrases metabolism, Interneurons physiology, Luminescent Agents metabolism, Mice, Cell Movement physiology, Cerebral Cortex physiology, Neurons physiology, Neurosciences methods
- Abstract
The cerebral cortex is one of the most intricate regions of the brain that requires elaborate cell migration patterns for its development. Experimental observations show that projection neurons migrate radially within the cortical wall, whereas interneurons migrate along multiple tangential paths to reach the developing cortex. Tight regulation of the cell migration processes ensures proper positioning and functional integration of neurons to specific cerebral cortical circuits. Disruption of neuronal migration often leads to cortical dysfunction and/or malformation associated with neurological disorders. Unveiling the molecular control of neuron migration is thus fundamental to understanding the physiological or pathological development of the cerebral cortex. In this unit, protocols allowing detailed analysis of patterns of migration of both interneurons and projection neurons under different experimental conditions (i.e., loss or gain of function) are presented., (Copyright © 2016 John Wiley & Sons, Inc.)
- Published
- 2016
- Full Text
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7. MicroRNA targeting of CoREST controls polarization of migrating cortical neurons.
- Author
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Volvert ML, Prévot PP, Close P, Laguesse S, Pirotte S, Hemphill J, Rogister F, Kruzy N, Sacheli R, Moonen G, Deiters A, Merkenschlager M, Chariot A, Malgrange B, Godin JD, and Nguyen L
- Subjects
- Animals, Cell Polarity physiology, Cells, Cultured, Co-Repressor Proteins, Mice, Mice, Transgenic, Neurons metabolism, Cell Movement physiology, Cerebral Cortex cytology, MicroRNAs metabolism, Nerve Tissue Proteins metabolism, Neurons cytology, Repressor Proteins metabolism
- Abstract
The migration of cortical projection neurons is a multistep process characterized by dynamic cell shape remodeling. The molecular basis of these changes remains elusive, and the present work describes how microRNAs (miRNAs) control neuronal polarization during radial migration. We show that miR-22 and miR-124 are expressed in the cortical wall where they target components of the CoREST/REST transcriptional repressor complex, thereby regulating doublecortin transcription in migrating neurons. This molecular pathway underlies radial migration by promoting dynamic multipolar-bipolar cell conversion at early phases of migration, and later stabilization of cell polarity to support locomotion on radial glia fibers. Thus, our work emphasizes key roles of some miRNAs that control radial migration during cerebral corticogenesis., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
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8. Alteration of rat fetal cerebral cortex development after prenatal exposure to polychlorinated biphenyls.
- Author
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Naveau E, Pinson A, Gérard A, Nguyen L, Charlier C, Thomé JP, Zoeller RT, Bourguignon JP, and Parent AS
- Subjects
- Animals, Cell Cycle drug effects, Cell Death, Cell Differentiation, Cell Movement, Cell Proliferation, Cerebral Cortex growth & development, Cerebral Cortex pathology, Down-Regulation, Female, Fetus, Neural Stem Cells cytology, Neural Stem Cells drug effects, Neurons pathology, Pregnancy, Prenatal Exposure Delayed Effects pathology, Prenatal Exposure Delayed Effects physiopathology, Rats, Thyroxine blood, Cerebral Cortex drug effects, Chlorodiphenyl (54% Chlorine) pharmacology, Endocrine Disruptors pharmacology, Environmental Pollutants pharmacology, Neurons drug effects, Prenatal Exposure Delayed Effects blood
- Abstract
Polychlorinated biphenyls (PCBs) are environmental contaminants that persist in environment and human tissues. Perinatal exposure to these endocrine disruptors causes cognitive deficits and learning disabilities in children. These effects may involve their ability to interfere with thyroid hormone (TH) action. We tested the hypothesis that developmental exposure to PCBs can concomitantly alter TH levels and TH-regulated events during cerebral cortex development: progenitor proliferation, cell cycle exit and neuron migration. Pregnant rats exposed to the commercial PCB mixture Aroclor 1254 ended gestation with reduced total and free serum thyroxine levels. Exposure to Aroclor 1254 increased cell cycle exit of the neuronal progenitors and delayed radial neuronal migration in the fetal cortex. Progenitor cell proliferation, cell death and differentiation rate were not altered by prenatal exposure to PCBs. Given that PCBs remain ubiquitous, though diminishing, contaminants in human systems, it is important that we further understand their deleterious effects in the brain.
- Published
- 2014
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9. Novel functions of core cell cycle regulators in neuronal migration.
- Author
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Godin JD and Nguyen L
- Subjects
- Animals, Cerebral Cortex cytology, Cyclin-Dependent Kinase Inhibitor p27 genetics, Humans, Neurons cytology, Cell Cycle physiology, Cell Movement physiology, Cerebral Cortex enzymology, Cyclin-Dependent Kinase Inhibitor p27 metabolism, Neurons enzymology
- Abstract
The cerebral cortex is one of the most intricate regions of the brain, which required elaborated cell migration patterns for its development. Experimental observations show that projection neurons migrate radially within the cortical wall, whereas interneurons migrate along multiple tangential paths to reach the developing cortex. Tight regulation of the cell migration processes ensures proper positioning and functional integration of neurons to specific cerebral cortical circuits. Disruption of neuronal migration often lead to cortical dysfunction and/or malformation associated with neurological disorders. Unveiling the molecular control of neuronal migration is thus fundamental to understand the physiological or pathological development of the cerebral cortex. Generation of functional cortical neurons is a complex and stratified process that relies on decision of neural progenitors to leave the cell cycle and generate neurons that migrate and differentiate to reach their final position in the cortical wall. Although accumulating work shed some light on the molecular control of neuronal migration, we currently do not have a comprehensive understanding of how cell cycle exit and migration/differentiation are coordinated at the molecular level. The current chapter tends to lift the veil on this issue by discussing how core cell cycle regulators, and in particular p27(Kip1) acts as a multifunctional protein to control critical steps of neuronal migration through activities that go far beyond cell cycle regulation.
- Published
- 2014
- Full Text
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10. p27(Kip1) is a microtubule-associated protein that promotes microtubule polymerization during neuron migration.
- Author
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Godin JD, Thomas N, Laguesse S, Malinouskaya L, Close P, Malaise O, Purnelle A, Raineteau O, Campbell K, Fero M, Moonen G, Malgrange B, Chariot A, Metin C, Besson A, and Nguyen L
- Subjects
- Animals, Biopolymers chemistry, Biopolymers metabolism, Mice, Microtubules chemistry, Neurons metabolism, Polymerization, Cell Movement, Cyclin-Dependent Kinase Inhibitor p27 metabolism, Microtubules metabolism, Neurons cytology
- Abstract
The migration of cortical interneurons is characterized by extensive morphological changes that result from successive cycles of nucleokinesis and neurite branching. Their molecular bases remain elusive, and the present work describes how p27(Kip1) controls cell-cycle-unrelated signaling pathways to regulate these morphological remodelings. Live imaging reveals that interneurons lacking p27(Kip1) show delayed tangential migration resulting from defects in both nucleokinesis and dynamic branching of the leading process. At the molecular level, p27(Kip1) is a microtubule-associated protein that promotes polymerization of microtubules in extending neurites, thereby contributing to tangential migration. Furthermore, we show that p27(Kip1) controls actomyosin contractions that drive both forward translocation of the nucleus and growth cone splitting. Thus, p27(Kip1) cell-autonomously controls nucleokinesis and neurite branching by regulating both actin and microtubule cytoskeletons., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
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11. Phosphorylation of SCG10/stathmin-2 determines multipolar stage exit and neuronal migration rate.
- Author
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Westerlund N, Zdrojewska J, Padzik A, Komulainen E, Björkblom B, Rannikko E, Tararuk T, Garcia-Frigola C, Sandholm J, Nguyen L, Kallunki T, Courtney MJ, and Coffey ET
- Subjects
- Animals, Calcium-Binding Proteins, Cerebral Cortex cytology, Cerebral Cortex embryology, Cerebral Cortex growth & development, Cerebral Cortex metabolism, Gene Expression Regulation, Intracellular Signaling Peptides and Proteins genetics, Mice, Mice, Knockout, Mitogen-Activated Protein Kinase 8 antagonists & inhibitors, Mitogen-Activated Protein Kinase 8 genetics, Mitogen-Activated Protein Kinase 8 metabolism, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Stathmin, Tubulin metabolism, Cell Movement physiology, Intracellular Signaling Peptides and Proteins metabolism, Neurons physiology
- Abstract
Cell migration is the consequence of the sum of positive and negative regulatory mechanisms. Although appropriate migration of neurons is a principal feature of brain development, the negative regulatory mechanisms remain obscure. We found that JNK1 was highly active in developing cortex and that selective inhibition of JNK in the cytoplasm markedly increased both the frequency of exit from the multipolar stage and radial migration rate and ultimately led to an ill-defined cellular organization. Moreover, regulation of multipolar-stage exit and radial migration in Jnk1(-/-) (also known as Mapk8) mice, resulted from consequential changes in phosphorylation of the microtubule regulator SCG10 (also called stathmin-2). Expression of an SCG10 mutant that mimics the JNK1-phosphorylated form restored normal migration in the brains of Jnk1(-/-) mouse embryos. These findings indicate that the phosphorylation of SCG10 by JNK1 is a fundamental mechanism that governs the transition from the multipolar stage and the rate of neuronal cell movement during cortical development.
- Published
- 2011
- Full Text
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12. Glial but not neuronal development in the cochleo-vestibular ganglion requires Sox10.
- Author
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Breuskin I, Bodson M, Thelen N, Thiry M, Borgs L, Nguyen L, Stolt C, Wegner M, Lefebvre PP, and Malgrange B
- Subjects
- Animals, Cochlea embryology, Mice, Mice, Knockout, SOXE Transcription Factors genetics, Spiral Ganglion cytology, Spiral Ganglion embryology, Vestibule, Labyrinth embryology, Cochlea innervation, Neuroglia physiology, Neurons physiology, SOXE Transcription Factors physiology, Spiral Ganglion metabolism, Vestibule, Labyrinth innervation
- Abstract
The cochleo-vestibular ganglion contains neural crest-derived glial cells and sensory neurons that are derived from the neurogenic otic placode. Little is known about the molecular mechanisms that regulate the tightly orchestrated development of this structure. Here, we report that Sox10, a high-mobility group DNA-binding domain transcription factor that is required for the proper development of neural crest cell derivatives, is specifically expressed in post-migratory neural crest cells in the cochleo-vestibular ganglion. Using Sox10-deficient mice, we demonstrate that this transcription factor is essential for the survival, but not the generation, of the post-migratory neural crest cells within the inner ear. In the absence of these neural crest-derived cells, we have investigated the survival of the otocyst-derived auditory neurons. Surprisingly, auditory neuron differentiation, sensory target innervation and survival are conserved despite the absence of glial cells. Moreover, brain-derived neurotrophic factor expression is increased in the hair cells of Sox10-deficient mice, a compensatory mechanism that may prevent spiral ganglion neuronal cell death. Taken together, these data suggest that in the absence of neural crest-derived glial cells, an increase trophic support from hair cells promotes the survival of spiral ganglion neurons in Sox10 mutant mice., (© 2010 The Authors. Journal Compilation © 2010 International Society for Neurochemistry.)
- Published
- 2010
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13. Huntingtin is required for mitotic spindle orientation and mammalian neurogenesis.
- Author
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Godin JD, Colombo K, Molina-Calavita M, Keryer G, Zala D, Charrin BC, Dietrich P, Volvert ML, Guillemot F, Dragatsis I, Bellaiche Y, Saudou F, Nguyen L, and Humbert S
- Subjects
- Animals, Cell Enlargement, Cells, Cultured, Drosophila Proteins, Drosophila melanogaster, HeLa Cells, Humans, Huntingtin Protein, Mice, Mice, Transgenic, Microtubule-Associated Proteins deficiency, Microtubules physiology, Microtubule-Associated Proteins physiology, Neurogenesis physiology, Neurons cytology, Neurons physiology, Spindle Apparatus physiology
- Abstract
Huntingtin is the protein mutated in Huntington's disease, a devastating neurodegenerative disorder. We demonstrate here that huntingtin is essential to control mitosis. Huntingtin is localized at spindle poles during mitosis. RNAi-mediated silencing of huntingtin in cells disrupts spindle orientation by mislocalizing the p150(Glued) subunit of dynactin, dynein, and the large nuclear mitotic apparatus NuMA protein. This leads to increased apoptosis following mitosis of adherent cells in vitro. In vivo inactivation of huntingtin by RNAi or by ablation of the Hdh gene affects spindle orientation and cell fate of cortical progenitors of the ventricular zone in mouse embryos. This function is conserved in Drosophila, the specific disruption of Drosophila huntingtin in neuroblast precursors leading to spindle misorientation. Moreover, Drosophila huntingtin restores spindle misorientation in mammalian cells. These findings reveal an unexpected role for huntingtin in dividing cells, with potential important implications in health and disease., ((c) 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
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14. Molecular layers underlying cytoskeletal remodelling during cortical development.
- Author
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Heng JI, Chariot A, and Nguyen L
- Subjects
- Animals, Cell Movement physiology, Cerebral Cortex cytology, Cerebral Cortex physiology, Humans, Cell Differentiation physiology, Cerebral Cortex embryology, Cytoskeleton physiology, Neurogenesis physiology, Neurons cytology
- Abstract
During neural development, the cytoskeleton of newborn neurons undergoes extensive and dynamic remodelling to facilitate the sequential steps of neurogenesis, cell migration and terminal differentiation. It is clear from studying the mechanisms that precipitate these functions that different configurations of the cytoskeleton prefigure the correct execution of each step and define cohorts of proteins the functions of which are indispensable for the control of neuronal migration but not terminal differentiation. These combinatorial protein functions are also predetermined by regulated gene expression and the precise subcellular localisation of their protein products. Here, we expand on this view in the context of recent data on how the cytoskeleton is regulated during the maturation of cortical neurons within the developing brain., (Copyright 2009 Elsevier Ltd. All rights reserved.)
- Published
- 2010
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15. EFHC1 interacts with microtubules to regulate cell division and cortical development.
- Author
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de Nijs L, Léon C, Nguyen L, Loturco JJ, Delgado-Escueta AV, Grisar T, and Lakaye B
- Subjects
- Analysis of Variance, Animals, Animals, Genetically Modified, Apoptosis physiology, Calcium-Binding Proteins genetics, Cell Line, Transformed, Cell Movement physiology, Electroporation methods, Embryo, Mammalian, Embryonic Stem Cells physiology, Female, Flow Cytometry methods, Green Fluorescent Proteins genetics, Humans, Immunoprecipitation methods, In Situ Nick-End Labeling methods, Mutation, Neuroglia metabolism, Pregnancy, Protein Binding, RNA Interference physiology, Rats, Rats, Wistar, Transfection methods, Calcium-Binding Proteins metabolism, Cell Division physiology, Cerebral Cortex cytology, Cerebral Cortex embryology, Cerebral Cortex growth & development, Microtubules metabolism, Neurons physiology
- Abstract
Mutations in the EFHC1 gene are linked to juvenile myoclonic epilepsy (JME), one of the most frequent forms of idiopathic generalized epilepsies. JME is associated with subtle alterations of cortical and subcortical architecture, but the underlying pathological mechanism remains unknown. We found that EFHC1 is a microtubule-associated protein involved in the regulation of cell division. In vitro, EFHC1 loss of function disrupted mitotic spindle organization, impaired M phase progression, induced microtubule bundling and increased apoptosis. EFHC1 impairment in the rat developing neocortex by ex vivo and in utero electroporation caused a marked disruption of radial migration. We found that this effect was a result of cortical progenitors failing to exit the cell cycle and defects in the radial glia scaffold organization and in the locomotion of postmitotic neurons. Therefore, we propose that EFHC1 is a regulator of cell division and neuronal migration during cortical development and that disruption of its functions leads to JME.
- Published
- 2009
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16. Period 2 regulates neural stem/progenitor cell proliferation in the adult hippocampus.
- Author
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Borgs L, Beukelaers P, Vandenbosch R, Nguyen L, Moonen G, Maquet P, Albrecht U, Belachew S, and Malgrange B
- Subjects
- Animals, Blotting, Western, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Cell Death physiology, Cells, Cultured, Dentate Gyrus growth & development, Hippocampus growth & development, Immunohistochemistry, In Situ Hybridization, In Situ Nick-End Labeling, Mice, Mice, Knockout, Neurogenesis genetics, Neurogenesis physiology, Nuclear Proteins deficiency, Nuclear Proteins genetics, Nuclear Proteins metabolism, Period Circadian Proteins, Transcription Factors deficiency, Transcription Factors genetics, Transcription Factors metabolism, Cell Cycle Proteins physiology, Cell Proliferation, Dentate Gyrus cytology, Hippocampus cytology, Neurons metabolism, Nuclear Proteins physiology, Stem Cells metabolism, Transcription Factors physiology
- Abstract
Background: Newborn granule neurons are generated from proliferating neural stem/progenitor cells and integrated into mature synaptic networks in the adult dentate gyrus of the hippocampus. Since light/dark variations of the mitotic index and DNA synthesis occur in many tissues, we wanted to unravel the role of the clock-controlled Period2 gene (mPer2) in timing cell cycle kinetics and neurogenesis in the adult DG., Results: In contrast to the suprachiasmatic nucleus, we observed a non-rhythmic constitutive expression of mPER2 in the dentate gyrus. We provide evidence that mPER2 is expressed in proliferating neural stem/progenitor cells (NPCs) and persists in early post-mitotic and mature newborn neurons from the adult DG. In vitro and in vivo analysis of a mouse line mutant in the mPer2 gene (Per2Brdm1), revealed a higher density of dividing NPCs together with an increased number of immature newborn neurons populating the DG. However, we showed that the lack of mPer2 does not change the total amount of mature adult-generated hippocampal neurons, because of a compensatory increase in neuronal cell death., Conclusion: Taken together, these data demonstrated a functional link between the constitutive expression of mPER2 and the intrinsic control of neural stem/progenitor cells proliferation, cell death and neurogenesis in the dentate gyrus of adult mice.
- Published
- 2009
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17. Elongator controls the migration and differentiation of cortical neurons through acetylation of alpha-tubulin.
- Author
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Creppe C, Malinouskaya L, Volvert ML, Gillard M, Close P, Malaise O, Laguesse S, Cornez I, Rahmouni S, Ormenese S, Belachew S, Malgrange B, Chapelle JP, Siebenlist U, Moonen G, Chariot A, and Nguyen L
- Subjects
- Acetylation, Animals, Cell Line, Cells, Cultured, Embryo, Mammalian cytology, Embryo, Mammalian metabolism, Female, Humans, Mice, Multienzyme Complexes metabolism, Neurogenesis, Cell Movement, Cerebral Cortex cytology, Histone Acetyltransferases metabolism, Neurons cytology, Tubulin metabolism
- Abstract
The generation of cortical projection neurons relies on the coordination of radial migration with branching. Here, we report that the multisubunit histone acetyltransferase Elongator complex, which contributes to transcript elongation, also regulates the maturation of projection neurons. Indeed, silencing of its scaffold (Elp1) or catalytic subunit (Elp3) cell-autonomously delays the migration and impairs the branching of projection neurons. Strikingly, neurons defective in Elongator show reduced levels of acetylated alpha-tubulin. Reduction of alpha-tubulin acetylation via expression of a nonacetylatable alpha-tubulin mutant leads to comparable defects in cortical neurons and suggests that alpha-tubulin is a target of Elp3. This is further supported by the demonstration that Elp3 promotes acetylation and counteracts HDAC6-mediated deacetylation of this substrate in vitro. Our results uncover alpha-tubulin as a target of the Elongator complex and suggest that a tight regulation of its acetylation underlies the maturation of cortical projection neurons.
- Published
- 2009
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18. Adult neurogenesis and the diseased brain.
- Author
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Vandenbosch R, Borgs L, Beukelaers P, Belachew S, Moonen G, Nguyen L, and Malgrange B
- Subjects
- Adult, Animals, Humans, Neurons pathology, Neurodegenerative Diseases pathology, Neurogenesis physiology, Neurons cytology
- Abstract
For a long time it was believed that the adult mammalian brain was completely unable to regenerate after insults. However, recent advances in the field of stem cell biology, including the identification of adult neural stem cells (NSCs) and evidence regarding a continuous production of neurons throughout life in the dentate gyrus (DG) and the subventricular zone of the lateral ventricles (SVZ), have provided new hopes for the development of novel therapeutic strategies to induce regeneration in the damaged brain. Moreover, proofs have accumulated this last decade that endogenous stem/progenitor cells of the adult brain have an intrinsic capacity to respond to brain disorders. Here, we first briefly summarize our current knowledge related to adult neurogenesis before focusing on the behaviour of adult neural stem/progenitors cells following stroke and seizure, and describe some of the molecular cues involved in the response of these cells to injury. In the second part, we outline the consequences of three main neurodegenerative disorders on adult neurogenesis and we discuss the potential therapeutic implication of adult neural stem/progenitors cells during the course of these diseases.
- Published
- 2009
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19. Neurogenin 2 controls cortical neuron migration through regulation of Rnd2.
- Author
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Heng JI, Nguyen L, Castro DS, Zimmer C, Wildner H, Armant O, Skowronska-Krawczyk D, Bedogni F, Matter JM, Hevner R, and Guillemot F
- Subjects
- 3' Untranslated Regions genetics, Animals, Basic Helix-Loop-Helix Transcription Factors deficiency, Basic Helix-Loop-Helix Transcription Factors genetics, Cell Shape, Cerebral Cortex embryology, Cerebral Cortex metabolism, Enhancer Elements, Genetic genetics, Gene Deletion, Gene Expression Regulation, Developmental, Mice, Nerve Tissue Proteins deficiency, Nerve Tissue Proteins genetics, RNA Interference, rho GTP-Binding Proteins deficiency, rho GTP-Binding Proteins genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Cell Movement, Cerebral Cortex cytology, Nerve Tissue Proteins metabolism, Neurons cytology, Neurons metabolism, rho GTP-Binding Proteins metabolism
- Abstract
Motility is a universal property of newly generated neurons. How cell migration is coordinately regulated with other aspects of neuron production is not well understood. Here we show that the proneural protein neurogenin 2 (Neurog2), which controls neurogenesis in the embryonic cerebral cortex, directly induces the expression of the small GTP-binding protein Rnd2 (ref. 3) in newly generated mouse cortical neurons before they initiate migration. Rnd2 silencing leads to a defect in radial migration of cortical neurons similar to that observed when the Neurog2 gene is deleted. Remarkably, restoring Rnd2 expression in Neurog2-mutant neurons is sufficient to rescue their ability to migrate. Our results identify Rnd2 as a novel essential regulator of neuronal migration in the cerebral cortex and demonstrate that Rnd2 is a major effector of Neurog2 function in the promotion of migration. Thus, a proneural protein controls the complex cellular behaviour of cell migration through a remarkably direct pathway involving the transcriptional activation of a small GTP-binding protein.
- Published
- 2008
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20. Characterization of the proneural gene regulatory network during mouse telencephalon development.
- Author
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Gohlke JM, Armant O, Parham FM, Smith MV, Zimmer C, Castro DS, Nguyen L, Parker JS, Gradwohl G, Portier CJ, and Guillemot F
- Subjects
- Algorithms, Animals, Bayes Theorem, Cell Adhesion genetics, Computational Biology, Embryo, Mammalian, Gene Expression Regulation, Developmental, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mutation, Signal Transduction genetics, Basic Helix-Loop-Helix Transcription Factors genetics, Gene Regulatory Networks, Nerve Tissue Proteins genetics, Neurons cytology, Telencephalon embryology
- Abstract
Background: The proneural proteins Mash1 and Ngn2 are key cell autonomous regulators of neurogenesis in the mammalian central nervous system, yet little is known about the molecular pathways regulated by these transcription factors., Results: Here we identify the downstream effectors of proneural genes in the telencephalon using a genomic approach to analyze the transcriptome of mice that are either lacking or overexpressing proneural genes. Novel targets of Ngn2 and/or Mash1 were identified, such as members of the Notch and Wnt pathways, and proteins involved in adhesion and signal transduction. Next, we searched the non-coding sequence surrounding the predicted proneural downstream effector genes for evolutionarily conserved transcription factor binding sites associated with newly defined consensus binding sites for Ngn2 and Mash1. This allowed us to identify potential novel co-factors and co-regulators for proneural proteins, including Creb, Tcf/Lef, Pou-domain containing transcription factors, Sox9, and Mef2a. Finally, a gene regulatory network was delineated using a novel Bayesian-based algorithm that can incorporate information from diverse datasets., Conclusion: Together, these data shed light on the molecular pathways regulated by proneural genes and demonstrate that the integration of experimentation with bioinformatics can guide both hypothesis testing and hypothesis generation.
- Published
- 2008
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21. CDK2 is dispensable for adult hippocampal neurogenesis.
- Author
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Vandenbosch R, Borgs L, Beukelaers P, Foidart A, Nguyen L, Moonen G, Berthet C, Kaldis P, Gallo V, Belachew S, and Malgrange B
- Subjects
- Animals, Apoptosis, Cell Differentiation, Cyclin-Dependent Kinase 2 genetics, Dentate Gyrus cytology, Dentate Gyrus enzymology, Dentate Gyrus physiology, Hippocampus cytology, Hippocampus enzymology, Mice, Mice, Knockout, Neurons cytology, Stem Cells cytology, Stem Cells physiology, Cyclin-Dependent Kinase 2 physiology, Hippocampus physiology, Neurons physiology
- Abstract
Granule neurons of the dentate gyrus (DG) of the hippocampus undergo continuous renewal throughout life. Among cell cycle regulators, cyclin-dependent kinase 2 (Cdk2) is considered as a major regulator of S-phase entry. We used Cdk2-deficient mice to decipher the requirement of Cdk2 for the generation of new neurons in the adult hippocampus. The quantification of cell cycle markers first revealed that the lack of Cdk2 activity does not influence spontaneous or seizure-induced proliferation of neural progenitor cells (NPC) in the adult DG. Using bromodeoxyuridine incorporation assays, we showed that the number of mature newborn granule neurons generated de novo was similar in both wild-type (WT) and Cdk2-deficient adult mice. Moreover, the apparent lack of cell output reduction in Cdk2(-/-) mice DG did not result from a reduction in apoptosis of newborn granule cells as analyzed by TUNEL assays. Our results therefore suggest that Cdk2 is dispensable for NPC proliferation, differentiation and survival of adult-born DG granule neurons in vivo. These data emphasize that functional redundancies between Cdks also occur in the adult brain at the level of neural progenitor cell cycle regulation during hippocampal neurogenesis.
- Published
- 2007
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22. Neurotransmitters regulate cell migration in the telencephalon.
- Author
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Heng JI, Moonen G, and Nguyen L
- Subjects
- Animals, Cell Differentiation physiology, Cell Proliferation, Humans, Neurons cytology, Receptors, Neurotransmitter metabolism, Signal Transduction physiology, Stem Cells cytology, Telencephalon cytology, Cell Movement physiology, Neurons metabolism, Neurotransmitter Agents metabolism, Stem Cells metabolism, Telencephalon embryology, Telencephalon metabolism
- Abstract
The complex cytoarchitectonic organization of the adult mammalian telencephalon reflects the elaborate patterns of cell migration that contribute to its generation. The migration by neurons in the CNS can broadly be divided into two categories: radial and tangential. Experimental observations in the telencephalon have shown that glutamatergic projection neurons are born in the progenitor compartment of the dorsal telencephalon and migrate radially to integrate the cortical plate, whereas most gamma-aminobutyric acid (GABA)ergic interneurons are generated in the ganglionic eminences and navigate through multiple tangential paths to settle into distinct telencephalic structures. Despite progress towards the understanding of the genetic determinants that specify the fate of neuronal progenitors, much remains unknown about the mechanisms that direct their migration into specific regions of the telencephalon. Interestingly, besides their function in synaptic transmission, neurotransmitters have been shown to promote several developmental processes that contribute to the establishment and maintenance of the CNS. In this respect, recent studies have highlighted a role for neurotransmitters through activation of their receptors in regulating cell migration in the telencephalon. This review summarizes and discusses the growing body of literature implicating neurotransmitters and their cognate receptors as part of a complex molecular machinery that regulate the migration of immature neurons in the telencephalon during development and in adulthood.
- Published
- 2007
- Full Text
- View/download PDF
23. Proneural bHLH and Brn proteins coregulate a neurogenic program through cooperative binding to a conserved DNA motif.
- Author
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Castro DS, Skowronska-Krawczyk D, Armant O, Donaldson IJ, Parras C, Hunt C, Critchley JA, Nguyen L, Gossler A, Göttgens B, Matter JM, and Guillemot F
- Subjects
- Amino Acid Sequence, Animals, Base Sequence, Basic Helix-Loop-Helix Transcription Factors genetics, Cell Differentiation, Cell Movement, Chick Embryo, Chromatin Immunoprecipitation, Electroporation, Gene Expression Regulation, Developmental, Intracellular Signaling Peptides and Proteins, Membrane Proteins metabolism, Mice, Mice, Transgenic, Molecular Sequence Data, Nerve Tissue Proteins genetics, Neurons metabolism, POU Domain Factors genetics, Promoter Regions, Genetic, Sequence Homology, Amino Acid, Sequence Homology, Nucleic Acid, Stem Cells metabolism, Transcription, Genetic, Transfection, Basic Helix-Loop-Helix Transcription Factors metabolism, DNA metabolism, Membrane Proteins genetics, Nerve Tissue Proteins metabolism, Neurons cytology, POU Domain Factors metabolism, Regulatory Sequences, Nucleic Acid physiology
- Abstract
Proneural proteins play a central role in vertebrate neurogenesis, but little is known of the genes that they regulate and of the factors that interact with proneural proteins to activate a neurogenic program. Here, we demonstrate that the proneural protein Mash1 and the POU proteins Brn1 and Brn2 interact on the promoter of the Notch ligand Delta1 and synergistically activate Delta1 transcription, a key step in neurogenesis. Overexpression experiments in vivo indicate that Brn2, like Mash1, regulates additional aspects of neurogenesis, including the division of progenitors and the differentiation and migration of neurons. We identify by in silico screening a number of additional candidate target genes, which are recognized by Mash1 and Brn proteins through a DNA-binding motif similar to that found in the Delta1 gene and present a broad range of activities. We thus propose that Mash1 synergizes with Brn factors to regulate multiple steps of neurogenesis.
- Published
- 2006
- Full Text
- View/download PDF
24. Coupling cell cycle exit, neuronal differentiation and migration in cortical neurogenesis.
- Author
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Nguyen L, Besson A, Roberts JM, and Guillemot F
- Subjects
- Animals, Cell Cycle, Cell Differentiation, Cell Movement, Cerebral Cortex growth & development, Cyclin-Dependent Kinase Inhibitor p27 physiology, Humans, Stem Cells cytology, Cerebral Cortex cytology, Neurons cytology
- Abstract
The generation of new neurons in the cerebral cortex requires that progenitor cells leave the cell cycle and activate specific programs of differentiation and migration. Genetic studies have identified some of the molecules controlling these cellular events, but how the different aspects of neurogenesis are integrated into a coherent developmental program remains unclear. One possible mechanism implicates multifunctional proteins that regulate, both cell cycle exit and cell differentiation.(1) A prime example is the cyclin-dependent kinase inhibitor p27(Kip1), which has recently been shown to function beyond cell cycle regulation and promote both neuronal differentiation and migration of newborn cortical neurons, through distinct and separable mechanisms. p27(Kip1) is therefore part of a machinery that couples the multiple events of neurogenesis in the cerebral cortex.
- Published
- 2006
- Full Text
- View/download PDF
25. A role for proneural genes in the maturation of cortical progenitor cells.
- Author
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Britz O, Mattar P, Nguyen L, Langevin LM, Zimmer C, Alam S, Guillemot F, and Schuurmans C
- Subjects
- Aging pathology, Aging physiology, Animals, Cell Aggregation, Cell Differentiation, Cell Movement, Cells, Cultured, In Vitro Techniques, Male, Mice, Neurons physiology, Organogenesis physiology, Stem Cells physiology, Basic Helix-Loop-Helix Transcription Factors metabolism, Cerebral Cortex cytology, Cerebral Cortex embryology, Nerve Tissue Proteins metabolism, Neurons cytology, Stem Cells cytology
- Abstract
We showed previously that the proneural genes Neurogenin1 (Ngn1) and Ngn2 are required to specify the phenotypes of early- and not late-born neurons in the neocortex, acting in part through repression of Mash1, a third cortically expressed proneural gene. The precise timing of Ngn1/2 specification activity was unexpected given these genes are expressed throughout cortical development, prompting us to search for a later function. Here we reveal that Ngn2 and Mash1 are expressed in a dynamic fashion, acquiring a cell cycle-biased, nonoverlapping distribution, with preferential expression in prospective basal progenitors, during mid corticogenesis. We also identified a new function for Ngn2 during this latter period, demonstrating that it is required to regulate the transit of cortical progenitors from the ventricular zone (VZ) to the subventricular zone. Notably, Ngn2 regulates progenitor maturation at least in part through repression of Mash1 as misexpression of Mash1 strongly enhanced progenitor cell exit from the VZ. Significantly, the ability of Mash1 to promote progenitor cell maturation occurred independently of its ability to respecify cortical cells and is thus a novel function for Mash1. Taken together, these data support a model whereby Ngn2 and Mash1 function together to regulate the zonal distribution of progenitors in the developing neocortex.
- Published
- 2006
- Full Text
- View/download PDF
26. p27kip1 independently promotes neuronal differentiation and migration in the cerebral cortex.
- Author
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Nguyen L, Besson A, Heng JI, Schuurmans C, Teboul L, Parras C, Philpott A, Roberts JM, and Guillemot F
- Subjects
- Animals, Base Sequence, Immunohistochemistry, In Situ Hybridization, Mice, Mice, Mutant Strains, Molecular Sequence Data, Cell Differentiation physiology, Cell Movement physiology, Cerebral Cortex cytology, Cyclin-Dependent Kinase Inhibitor p27 physiology, Neurons cytology
- Abstract
The generation of neurons by progenitor cells involves the tight coordination of multiple cellular activities, including cell cycle exit, initiation of neuronal differentiation, and cell migration. The mechanisms that integrate these different events into a coherent developmental program are not well understood. Here we show that the cyclin-dependent kinase inhibitor p27(Kip1) plays an important role in neurogenesis in the mouse cerebral cortex by promoting the differentiation and radial migration of cortical projection neurons. Importantly, these two functions of p27(Kip1) involve distinct activities, which are independent of its role in cell cycle regulation. p27(Kip1) promotes neuronal differentiation by stabilizing Neurogenin2 protein, an activity carried by the N-terminal half of the protein. p27(Kip1) promotes neuronal migration by blocking RhoA signaling, an activity that resides in its C-terminal half. Thus, p27(Kip1) plays a key role in cortical development, acting as a modular protein that independently regulates and couples multiple cellular pathways contributing to neurogenesis.
- Published
- 2006
- Full Text
- View/download PDF
27. Coupling of cell migration with neurogenesis by proneural bHLH factors.
- Author
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Ge W, He F, Kim KJ, Blanchi B, Coskun V, Nguyen L, Wu X, Zhao J, Heng JI, Martinowich K, Tao J, Wu H, Castro D, Sobeih MM, Corfas G, Gleeson JG, Greenberg ME, Guillemot F, and Sun YE
- Subjects
- Actins chemistry, Animals, Basic Helix-Loop-Helix Transcription Factors metabolism, Blotting, Western, Cell Differentiation, Cell Movement, Cerebral Cortex pathology, Chromatin Immunoprecipitation, Cytoskeleton metabolism, DNA chemistry, Doublecortin Domain Proteins, Down-Regulation, Electroporation, GTP Phosphohydrolases metabolism, Mice, Mice, Transgenic, Microscopy, Fluorescence, Microtubule-Associated Proteins biosynthesis, Microtubules metabolism, Mutation, Nerve Tissue Proteins biosynthesis, Nerve Tissue Proteins metabolism, Neuropeptides biosynthesis, Protein Binding, Reverse Transcriptase Polymerase Chain Reaction, Transfection, Up-Regulation, rhoA GTP-Binding Protein metabolism, DNA-Binding Proteins chemistry, DNA-Binding Proteins physiology, Gene Expression Regulation, Neurons metabolism, Transcription Factors chemistry, Transcription Factors physiology
- Abstract
After cell birth, almost all neurons in the mammalian central nervous system migrate. It is unclear whether and how cell migration is coupled with neurogenesis. Here we report that proneural basic helix-loop-helix (bHLH) transcription factors not only initiate neuronal differentiation but also potentiate cell migration. Mechanistically, proneural bHLH factors regulate the expression of genes critically involved in migration, including down-regulation of RhoA small GTPase and up-regulation of doublecortin and p35, which, in turn, modulate the actin and microtubule cytoskeleton assembly and enable newly generated neurons to migrate. In addition, we report that several DNA-binding-deficient proneural genes that fail to initiate neuronal differentiation still activate migration, whereas a different mutation of a proneural gene that causes a failure in initiating cell migration still leads to robust neuronal differentiation. Collectively, these data suggest that transcription programs for neurogenesis and migration are regulated by bHLH factors through partially distinct mechanisms.
- Published
- 2006
- Full Text
- View/download PDF
28. Striatal PSA-NCAM(+) precursor cells from the newborn rat express functional glycine receptors.
- Author
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Nguyen L, Malgrange B, Breuskin I, Lallemend F, Hans G, Moonen G, Belachew S, and Rigo JM
- Subjects
- Animals, Animals, Newborn, Cells, Cultured, Corpus Striatum cytology, Glycine pharmacology, Immunohistochemistry, Membrane Potentials drug effects, Membrane Potentials physiology, Neurons cytology, Rats, Rats, Wistar, Receptors, Glycine drug effects, Stem Cells cytology, Stem Cells drug effects, Strychnine pharmacology, Corpus Striatum metabolism, Neural Cell Adhesion Molecule L1 metabolism, Neurons metabolism, Receptors, Glycine metabolism, Sialic Acids metabolism, Stem Cells metabolism
- Abstract
Immunocytochemical analysis showed that ionotropic glycine receptors are expressed in neurogenic progenitors purified from the newborn rat striatum and expressing the polysialylated form of the neural cell adhesion molecule, both in vitro and in situ. To ascertain whether glycine receptors were functional in vitro, whole-cell patch-clamp recordings demonstrated that glycine triggers inward strychnine-sensitive currents in the majority of these cells. Moreover, we found that glycine receptors expressed by these neurogenic progenitors display intermediate electrophysiological characteristics between those of glycine receptors expressed by neural stem cells and by mature interneurons from the rat striatum. Altogether, the present data show that functional strychnine-sensitive glycine receptors are expressed in neurogenic progenitors purified from the newborn rat striatum.
- Published
- 2004
- Full Text
- View/download PDF
29. Functional glycine receptors are expressed by postnatal nestin-positive neural stem/progenitor cells.
- Author
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Nguyen L, Malgrange B, Belachew S, Rogister B, Rocher V, Moonen G, and Rigo JM
- Subjects
- Animals, Animals, Newborn, Cell Differentiation drug effects, Cell Membrane drug effects, Cell Membrane ultrastructure, Cells, Cultured, Central Nervous System cytology, Central Nervous System metabolism, Chloride Channels drug effects, Chloride Channels metabolism, Dose-Response Relationship, Drug, GABA Antagonists pharmacology, Gene Expression Regulation, Developmental physiology, Glycine metabolism, Membrane Potentials drug effects, Membrane Potentials physiology, Nestin, Neural Inhibition drug effects, Neural Inhibition physiology, Neurons cytology, Neurons drug effects, Picrotoxin pharmacology, Rats, Rats, Wistar, Receptors, Glycine agonists, Spheroids, Cellular drug effects, Spheroids, Cellular metabolism, Stem Cells cytology, Stem Cells drug effects, Strychnine pharmacology, Synaptic Transmission physiology, Cell Differentiation physiology, Cell Membrane metabolism, Central Nervous System growth & development, Intermediate Filament Proteins metabolism, Nerve Tissue Proteins, Neurons metabolism, Receptors, Glycine metabolism, Stem Cells metabolism
- Abstract
Multipotent neural stem and progenitor cells (NS/PCs) are well-established cell subpopulations occurring in the developing, and also in the mature mammalian nervous systems. Trophic and transcription factors are currently the main signals known to influence the development and the commitment of NS/PCs and their progeny. However, recent studies suggest that neurotransmitters could also contribute to neural development. In that respect, rodent-cultured embryonic NS/PCs have been reported to express functional neurotransmitter receptors. No similar investigation has, however, been made in postnatal and/or in adult rodent brain stem cells. In this study, using RT-PCR and immunocytochemical methods, we show that alpha(1)-, alpha(2)- and beta-subunit mRNAs and alpha-subunit proteins of the glycine ionotropic receptor are expressed by 80.5 +/- 0.9% of postnatal rat striatum-derived, nestin-positive cells within cultured neurospheres. Whole-cell patch-clamp experiments further demonstrated that glycine triggers in 33.5% of these cells currents that can be reversibly blocked by strychnine and picrotoxin. This demonstrates that NS/PCs express functional glycine receptors, the consequence(s) of their activation remaining unknown.
- Published
- 2002
- Full Text
- View/download PDF
30. Endocannabinoid Signaling Controls Pyramidal Cell Specification and Long-Range Axon Patterning
- Author
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Mulder, Jan, Aguado, Tania, Keimpema, Erik, Barabás, Klaudia, Rosado, Carlos J. Ballester, Nguyen, Laurent, Monory, Krisztina, Marsicano, Giovanni, Di Marzo, Vincenzo, Hurd, Yasmin L., Guillemot, Francois, Mackie, Ken, Lutz, Beat, Guzmán, Manuel, Lu, Hui-Chen, Galve-Roperh, Ismael, and Harkany, Tibor
- Published
- 2008
- Full Text
- View/download PDF
31. ATAT1-enriched vesicles promote microtubule acetylation via axonal transport
- Author
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Even, Aviel, Morelli, Giovanni, Broix, Loïc, Scaramuzzino, Chiara, Turchetto, Silvia, Gladwyn-Ng, Ivan, Le Bail, Romain, Shilian, Michal, Freeman, Stephen, Magiera, Maria M., Jijumon, A. S., Krusy, Nathalie, Malgrange, Brigitte, Brone, Bert, Dietrich, Paula, Dragatsis, Ioannis, Janke, Carsten, Saudou, Frédéric, Weil, Miguel, and Nguyen, Laurent
- Subjects
Male ,Inhibitor ,Leads ,Induced Pluripotent Stem Cells ,Axonal Transport ,Microtubules ,Mice ,Tubulin Acetyltransferase 1 ,Acetyltransferases ,Tubulin ,Mechanisms ,Animals ,Humans ,Research Articles ,Mice, Knockout ,Neurons ,Energy ,Mec-17 ,SciAdv r-articles ,Life Sciences ,Acetylation ,Cell Biology ,Binding ,Drosophila melanogaster ,HEK293 Cells ,nervous system ,Larva ,Microtubule Proteins ,Deficiency ,Female ,Glycolysis ,Locomotion ,Model ,Research Article ,HeLa Cells - Abstract
The axonal transport of vesicles promotes microtubule acetylation across species., Microtubules are polymerized dimers of α- and β-tubulin that underlie a broad range of cellular activities. Acetylation of α-tubulin by the acetyltransferase ATAT1 modulates microtubule dynamics and functions in neurons. However, it remains unclear how this enzyme acetylates microtubules over long distances in axons. Here, we show that loss of ATAT1 impairs axonal transport in neurons in vivo, and cell-free motility assays confirm a requirement of α-tubulin acetylation for proper bidirectional vesicular transport. Moreover, we demonstrate that the main cellular pool of ATAT1 is transported at the cytosolic side of neuronal vesicles that are moving along axons. Together, our data suggest that axonal transport of ATAT1-enriched vesicles is the predominant driver of α-tubulin acetylation in axons.
- Published
- 2019
32. Proliferation of hippocampal progenitors relies on p27-dependent regulation of Cdk6 kinase activity.
- Author
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Caron, Nicolas, Genin, Emmanuelle C., Marlier, Quentin, Verteneuil, Sébastien, Beukelaers, Pierre, Morel, Laurence, Hu, Miaofen G., Hinds, Philip W., Nguyen, Laurent, Vandenbosch, Renaud, and Malgrange, Brigitte
- Subjects
PROGENITOR cells ,NEURAL stem cells ,CYCLIN-dependent kinases ,KINASES ,CELL cycle proteins ,NEURONS - Abstract
Neural stem cells give rise to granule dentate neurons throughout life in the hippocampus. Upon activation, these stem cells generate fast proliferating progenitors that complete several rounds of divisions before differentiating into neurons. Although the mechanisms regulating the activation of stem cells have been intensively studied, little attention has been given so far to the intrinsic machinery allowing the expansion of the progenitor pool. The cell cycle protein Cdk6 positively regulates the proliferation of hippocampal progenitors, but the mechanism involved remains elusive. Whereas Cdk6 functions primarily as a cell cycle kinase, it can also act as transcriptional regulator in cancer cells and hematopoietic stem cells. Using mouse genetics, we show here that the function of Cdk6 in hippocampal neurogenesis relies specifically on its kinase activity. The present study also reveals a specific regulatory mechanism for Cdk6 in hippocampal progenitors. In contrast to the classical model of the cell cycle, we observe that the Cip/Kip family member p27, rather than the Ink4 family, negatively regulates Cdk6 in the adult hippocampus. Altogether, our data uncover a unique, cell type-specific regulatory mechanism controlling the expansion of hippocampal progenitors, where Cdk6 kinase activity is modulated by p27. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
33. Early neuronal inhibition sculpts adult cortical interhemispheric connectivity.
- Author
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Javier-Torrent, Míriam, Bonafina, Antonela, and Nguyen, Laurent
- Subjects
- *
NEUROPLASTICITY , *NEURAL development , *CEREBRAL cortex , *INTERNEURONS , *NEURONS - Abstract
The maturation of cerebral cortical networks during early life involves a major reorganization of long-range axonal connections. In a recent study, Bragg-Gonzalo, Aguilera, et al. discovered that in mice, the interhemispheric connections sent by S1L4 callosal projection neurons are pruned via the tight control of their ipsilateral synaptic integration, which relies on the early activity of specific interneurons. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
34. Cycling or not cycling: cell cycle regulatory molecules and adult neurogenesis.
- Author
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Beukelaers, Pierre, Vandenbosch, Renaud, Caron, Nicolas, Nguyen, Laurent, Moonen, Gustave, and Malgrange, Brigitte
- Subjects
CELL cycle regulation ,DEVELOPMENTAL neurobiology ,NEURONS ,DENTATE gyrus ,OLFACTORY bulb ,CYCLIN-dependent kinases - Abstract
The adult brain most probably reaches its highest degree of plasticity with the lifelong generation and integration of new neurons in the hippocampus and olfactory system. Neural precursor cells (NPCs) residing both in the subgranular zone of the dentate gyrus and in the subventricular zone of the lateral ventricles continuously generate neurons that populate the dentate gyrus and the olfactory bulb, respectively. The regulation of NPC proliferation in the adult brain has been widely investigated in the past few years. Yet, the intrinsic cell cycle machinery underlying NPC proliferation remains largely unexplored. In this review, we discuss the cell cycle components that are involved in the regulation of NPC proliferation in both neurogenic areas of the adult brain. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
35. Expression patterns of miR-96, miR-182 and miR-183 in the developing inner ear
- Author
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Sacheli, Rosalie, Nguyen, Laurent, Borgs, Laurence, Vandenbosch, Renaud, Bodson, Morgan, Lefebvre, Philippe, and Malgrange, Brigitte
- Subjects
- *
GENE expression , *INNER ear , *MESSENGER RNA , *GENETIC code , *GENE targeting , *DEVELOPMENTAL biology , *IN situ hybridization - Abstract
Abstract: MicroRNAs (miRNAs) constitute a class of small non-coding endogenous RNAs that downregulate gene expression by binding to 3′ untranslated region (UTR) of target messenger RNAs. Although they have been found to regulate developmental and physiological processes in several organs and tissues, their role in the regulation of the inner ear transcriptome remains unknown. In this report, we have performed systematic in situ hybridizations to analyze the temporal and spatial distribution of three miRNAs (miR-96, miR-182 and miR-183) that are likely to arise from a single precursor RNA during the development and the maturation of the cochlea. Strikingly, we found that the expression of miR-96, miR-182 and miR-183 was highly dynamic during the development of the cochlea, from the patterning to the differentiation of the main cochlear structures. [Copyright &y& Elsevier]
- Published
- 2009
- Full Text
- View/download PDF
36. p27kip1 independently promotes neuronal differentiation and migration in the cerebral cortex.
- Author
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Nguyen, Laurent, Besson, Arnaud, Ik-Tsen Heng, Julian, Schuurmans, Carol, Teboul, Lydia, Parras, Carlos, Philpott, Anna, Roberts, James M., and Guillemot, François
- Subjects
- *
NEURONS , *CELL migration , *CELL differentiation , *MORPHOGENESIS , *CELLS - Abstract
The generation of neurons by progenitor cells involves the tight coordination of multiple cellular activities, including cell cycle exit, initiation of neuronal differentiation, and cell migration. The mechanisms that integrate these different events into a coherent developmental program are not well understood. Here we show that the cyclin-dependent kinase inhibitor p27Kip1 plays an important role in neurogenesis in the mouse cerebral cortex by promoting the differentiation and radial migration of cortical projection neurons. Importantly, these two functions of p27Kip1 involve distinct activities, which are independent of its role in cell cycle regulation. p27Kip1 promotes neuronal differentiation by stabilizing Neurogenin2 protein, an activity carried by the N-terminal half of the protein. p27Kip1 promotes neuronal migration by blocking RhoA signaling, an activity that resides in its C-terminal half. Thus, p27Kip1 plays a key role in cortical development, acting as a modular protein that independently regulates and couples multiple cellular pathways contributing to neurogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2006
37. Phosphorylation of Neurogenin2 Specifies the Migration Properties and the Dendritic Morphology of Pyramidal Neurons in the Neocortex
- Author
-
Hand, Randal, Bortone, Dante, Mattar, Pierre, Nguyen, Laurent, Heng, Julian Ik-Tsen, Guerrier, Sabrice, Boutt, Elizabeth, Peters, Eldon, Barnes, Anthony P., Parras, Carlos, Schuurmans, Carol, Guillemot, François, and Polleux, Franck
- Subjects
- *
CHEMICAL reactions , *CEREBRAL cortex , *NEURONS , *TRANSCRIPTION factors - Abstract
Summary: The molecular mechanisms specifying the dendritic morphology of different neuronal subtypes are poorly understood. Here we demonstrate that the bHLH transcription factor Neurogenin2 (Ngn2) is both necessary and sufficient for specifying the dendritic morphology of pyramidal neurons in vivo by specifying the polarity of its leading process during the initiation of radial migration. The ability of Ngn2 to promote a polarized leading process outgrowth requires the phosphorylation of a single tyrosine residue at position 241, an event that is neither involved in Ngn2 direct transactivation properties nor its proneural function. Interestingly, the migration defect observed in the Ngn2 knockout mouse and in progenitors expressing the Ngn2Y241F mutation can be rescued by inhibiting the activity of the small-GTPase RhoA in cortical progenitors. Our results demonstrate that Ngn2 coordinates the acquisition of the radial migration properties and the unipolar dendritic morphology characterizing pyramidal neurons through molecular mechanisms distinct from those mediating its proneural activity. [Copyright &y& Elsevier]
- Published
- 2005
- Full Text
- View/download PDF
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