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34 results on '"Marthe Vilotte"'

1. Massive detection of cryptic recessive genetic defects in dairy cattle mining millions of life histories

Author

Florian Besnard, Ana Guintard, Cécile Grohs, Laurence Guzylack-Piriou, Margarita Cano, Clémentine Escouflaire, Chris Hozé, Hélène Leclerc, Thierry Buronfosse, Lucie Dutheil, Jeanlin Jourdain, Anne Barbat, Sébastien Fritz, Marie-Christine Deloche, Aude Remot, Blandine Gaussères, Adèle Clément, Marion Bouchier, Elise Contat, Anne Relun, Vincent Plassard, Julie Rivière, Christine Péchoux, Marthe Vilotte, Camille Eche, Claire Kuchly, Mathieu Charles, Arnaud Boulling, Guillaume Viard, Stéphanie Minéry, Sarah Barbey, Clément Birbes, Coralie Danchin-Burge, Frédéric Launay, Sophie Mattalia, Aurélie Allais-Bonnet, Bérangère Ravary, Yves Millemann, Raphaël Guatteo, Christophe Klopp, Christine Gaspin, Carole Iampietro, Cécile Donnadieu, Denis Milan, Marie-Anne Arcangioli, Mekki Boussaha, Gilles Foucras, Didier Boichard, and Aurélien Capitan

Subjects
Data science, Recessive genetic defects, Livestock, Large-scale genotyping, Whole-genome sequencing, Inbreeding depression, Biology (General), QH301-705.5, Genetics, QH426-470
Abstract

Abstract Background Dairy cattle breeds are populations of limited effective size, subject to recurrent outbreaks of recessive defects that are commonly studied using positional cloning. However, this strategy, based on the observation of animals with characteristic features, may overlook a number of conditions, such as immune or metabolic genetic disorders, which may be confused with pathologies of environmental etiology. Results We present a data mining framework specifically designed to detect recessive defects in livestock that have been previously missed due to a lack of specific signs, incomplete penetrance, or incomplete linkage disequilibrium. This approach leverages the massive data generated by genomic selection. Its basic principle is to compare the observed and expected numbers of homozygotes for sliding haplotypes in animals with different life histories. Within three cattle breeds, we report 33 new loci responsible for increased risk of juvenile mortality and present a series of validations based on large-scale genotyping, clinical examination, and functional studies for candidate variants affecting the NOA1, RFC5, and ITGB7 genes. In particular, we describe disorders associated with NOA1 and RFC5 mutations for the first time in vertebrates. Conclusions The discovery of these many new defects will help to characterize the genetic basis of inbreeding depression, while their management will improve animal welfare and reduce losses to the industry.

Published
2024
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2. Malignant features of minipig melanomas prior to spontaneous regression

Author

Héloïse Débare, Fany Blanc, Guillaume Piton, Jean-Jacques Leplat, Silvia Vincent-Naulleau, Julie Rivière, Marthe Vilotte, Sylvain Marthey, Jérôme Lecardonnel, Jean-Luc Coville, Jordi Estellé, Andrea Rau, Emmanuelle Bourneuf, and Giorgia Egidy

Subjects
Medicine, Science
Abstract

Abstract In MeLiM minipigs, melanomas develop around birth, can metastasize, and have histopathologic characteristics similar to humans. Interestingly, MeLiM melanomas eventually regress. This favorable outcome raises the question of their malignancy, which we investigated. We clinically followed tens of tumors from onset to first signs of regression. Transcriptome analysis revealed an enrichment of all cancer hallmarks in melanomas, although no activating or suppressing somatic mutation were found in common driver genes. Analysis of tumor cell genomes revealed high mutation rates without UV signature. Canonical proliferative, survival and angiogenic pathways were detected in MeLiM tumor cells all along progression stages. Functionally, we show that MeLiM melanoma cells are capable to grow in immunocompromised mice, with serial passages and for a longer time than in MeLiM pigs. Pigs set in place an immune response during progression with dense infiltration by myeloid cells while melanoma cells are deficient in B2M expression. To conclude, our data on MeLiM melanomas reveal several malignancy characteristics. The combination of these features with the successful spontaneous regression of these tumors make it an outstanding model to study an efficient anti-tumor immune response.

Published
2024
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3. Wnt, glucocorticoid and cellular prion protein cooperate to drive a mesenchymal phenotype with poor prognosis in colon cancer

Author

Sophie Mouillet-Richard, Angélique Gougelet, Bruno Passet, Camille Brochard, Delphine Le Corre, Caterina Luana Pitasi, Camille Joubel, Marine Sroussi, Claire Gallois, Julien Lavergne, Johan Castille, Marthe Vilotte, Nathalie Daniel-Carlier, Camilla Pilati, Aurélien de Reyniès, Fatima Djouadi, Sabine Colnot, Thierry André, Julien Taieb, Jean-Luc Vilotte, Béatrice Romagnolo, and Pierre Laurent-Puig

Subjects
Colon cancer, Prion protein, Wnt-β-catenin, Glucocorticoid receptor, Molecular classification, Medicine
Abstract

Abstract Background The mesenchymal subtype of colorectal cancer (CRC), associated with poor prognosis, is characterized by abundant expression of the cellular prion protein PrPC, which represents a candidate therapeutic target. How PrPC is induced in CRC remains elusive. This study aims to elucidate the signaling pathways governing PrPC expression and to shed light on the gene regulatory networks linked to PrPC. Methods We performed in silico analyses on diverse datasets of in vitro, ex vivo and in vivo models of mouse CRC and patient cohorts. We mined ChIPseq studies and performed promoter analysis. CRC cell lines were manipulated through genetic and pharmacological approaches. We created mice combining conditional inactivation of Apc in intestinal epithelial cells and overexpression of the human prion protein gene PRNP. Bio-informatic analyses were carried out in two randomized control trials totalizing over 3000 CRC patients. Results In silico analyses combined with cell-based assays identified the Wnt-β-catenin and glucocorticoid pathways as upstream regulators of PRNP expression, with subtle differences between mouse and human. We uncover multiple feedback loops between PrPC and these two pathways, which translate into an aggravation of CRC pathogenesis in mouse. In stage III CRC patients, the signature defined by PRNP-CTNNB1-NR3C1, encoding PrPC, β-catenin and the glucocorticoid receptor respectively, is overrepresented in the poor-prognosis, mesenchymal subtype and associates with reduced time to recurrence. Conclusions An unleashed PrPC-dependent vicious circle is pathognomonic of poor prognosis, mesenchymal CRC. Patients from this aggressive subtype of CRC may benefit from therapies targeting the PRNP-CTNNB1-NR3C1 axis.

Published
2024
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4. Integrin alpha 6 homozygous splice-site mutation causes a new form of junctional epidermolysis bullosa in Charolais cattle

Author

Mekki Boussaha, Arnaud Boulling, Valérie Wolgust, Lorraine Bourgeois-Brunel, Pauline Michot, Cécile Grohs, Nicolas Gaiani, Pierre-Yves Grivaud, Hélène Leclerc, Coralie Danchin-Burge, Marthe Vilotte, Julie Rivière, Didier Boichard, Jean-Marie Gourreau, and Aurélien Capitan

Subjects
Animal culture, SF1-1100, Genetics, QH426-470
Abstract

Abstract Background Inherited epidermolysis bullosa (EB) is a group of painful and life-threatening genetic disorders that are characterized by mechanically induced blistering of the skin and mucous membranes. Congenital skin fragility resembling EB was recently reported in three Charolais calves born in two distinct herds from unaffected parents. Phenotypic and genetic analyses were carried out to describe this condition and its molecular etiology. Results Genealogical, pathological and histological investigations confirmed the diagnosis of recessive EB. However, the affected calves showed milder clinical signs compared to another form of EB, which was previously reported in the same breed and is caused by a homozygous deletion of the ITGB4 gene. Homozygosity mapping followed by analysis of the whole-genome sequences of two cases and 5031 control individuals enabled us to prioritize a splice donor site of ITGA6 (c.2160 + 1G > T; Chr2 g.24112740C > A) as the most compelling candidate variant. This substitution showed a perfect genotype–phenotype correlation in the two affected pedigrees and was found to segregate only in Charolais, and at a very low frequency (f = 1.6 × 10−4) after genotyping 186,154 animals from 15 breeds. Finally, RT-PCR analyses revealed increased retention of introns 14 and 15 of the ITGA6 gene in a heterozygous mutant cow compared with a matched control. The mutant mRNA is predicted to cause a frameshift (ITGA6 p.I657Mfs1) that affects the assembly of the integrin α6β4 dimer and its correct anchoring to the cell membrane. This dimer is a key component of the hemidesmosome anchoring complex, which ensures the attachment of basal epithelial cells to the basal membrane. Based on these elements, we arrived at a diagnosis of junctional EB. Conclusions We report a rare example of partial phenocopies observed in the same breed and due to mutations that affect two members of the same protein dimer, and provide the first evidence of an ITGA6 mutation that causes EB in livestock species.

Published
2023
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5. Beneficial Effects of Lactobacilli Species on Intestinal Homeostasis in Low-Grade Inflammation and Stress Rodent Models and Their Implication in the Modulation of the Adhesive Junctional Complex

Author

Célia Chamignon, Geoffroy Mallaret, Julie Rivière, Marthe Vilotte, Sead Chadi, Alejandra de Moreno de LeBlanc, Jean Guy LeBlanc, Frédéric Antonio Carvalho, Marco Pane, Pierre-Yves Mousset, Philippe Langella, Sophie Lafay, and Luis G. Bermúdez-Humarán

Subjects
leaky gut, chronic diseases, barrier functions, probiotics, Lactobacillus, Microbiology, QR1-502
Abstract

Intestinal barrier integrity is essential in order to maintain the homeostasis of mucosal functions and efficient defensive reactions against chemical and microbial challenges. An impairment of the intestinal barrier has been observed in several chronic diseases. The gut microbiota and its impact on intestinal homeostasis is well described and numerous studies suggest the ability of some probiotic strains to protect the intestinal epithelial integrity and host homeostasis. In this work, we aimed to assess the beneficial effects of three Lactobacillus strains (Lacticaseibacillus rhamnosus LR04, Lacticaseibacillus casei LC03, and Lactiplantibacillus plantarum CNCM I-4459) and their mechanism of action in low-grade inflammation or neonatal maternal separation models in mice. We compared the impact of these strains to that of the well-known probiotic Lacticaseibacillus rhamnosus GG. Our results demonstrated that the three strains have the potential to restore the barrier functions by (i) increasing mucus production, (ii) restoring normal permeability, and (iii) modulating colonic hypersensitivity. Moreover, gene expression analysis of junctional proteins revealed the implication of Claudin 2 and Cingulin in the mechanisms that underlie the interactions between the strains and the host. Taken together, our data suggest that LR04, CNCM I-4459, and LC03 restore the functions of an impaired intestinal barrier.

Published
2023
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6. CEP250 is Required for Maintaining Centrosome Cohesion in the Germline and Fertility in Male Mice

Author

Sandrine Floriot, Laura Bellutti, Johan Castille, Pauline Moison, Sébastien Messiaen, Bruno Passet, Laurent Boulanger, Abdelhak Boukadiri, Sophie Tourpin, Christian Beauvallet, Marthe Vilotte, Julie Riviere, Christine Péchoux, Maud Bertaud, Jean-Luc Vilotte, and Gabriel Livera

Subjects
centrosome, spermatogenesis, meiosis, DNA damage, oogenesis, Biology (General), QH301-705.5
Abstract

Male gametogenesis involves both mitotic divisions to amplify germ cell progenitors that gradually differentiate and meiotic divisions. Centrosomal regulation is essential for both types of divisions, with centrioles remaining tightly paired during the interphase. Here, we generated and characterized the phenotype of mutant mice devoid of Cep250/C-Nap1, a gene encoding for a docking protein for fibers linking centrioles, and characterized their phenotype. The Cep250-/- mice presented with no major defects, apart from male infertility due to a reduction in the spermatogonial pool and the meiotic blockade. Spermatogonial stem cells expressing Zbtb16 were not affected, whereas the differentiating spermatogonia were vastly lost. These cells displayed abnormal γH2AX-staining, accompanied by an increase in the apoptotic rate. The few germ cells that survived at this stage, entered the meiotic prophase I and were arrested at a pachytene-like stage, likely due to synapsis defects and the unrepaired DNA double-strand breaks. In these cells, centrosomes split up precociously, with γ-tubulin foci being separated whereas these were closely associated in wild-type cells. Interestingly, this lack of cohesion was also observed in wild-type female meiocytes, likely explaining the normal fertility of Cep250-/- female mice. Taken together, this study proposes a specific requirement of centrosome cohesion in the male germline, with a crucial role of CEP250 in both differentiating spermatogonia and meiotic spermatocytes.

Published
2022
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7. Bovine and murine models highlight novel roles for SLC25A46 in mitochondrial dynamics and metabolism, with implications for human and animal health.

Author

Amandine Duchesne, Anne Vaiman, Johan Castille, Christian Beauvallet, Pauline Gaignard, Sandrine Floriot, Sabrina Rodriguez, Marthe Vilotte, Laurent Boulanger, Bruno Passet, Olivier Albaric, François Guillaume, Abdelhak Boukadiri, Laurence Richard, Maud Bertaud, Edouard Timsit, Raphaël Guatteo, Florence Jaffrézic, Pierre Calvel, Louise Helary, Rachid Mahla, Diane Esquerré, Christine Péchoux, Sophie Liuu, Jean-Michel Vallat, Didier Boichard, Abdelhamid Slama, and Jean-Luc Vilotte

Subjects
Genetics, QH426-470
Abstract

Neuropathies are neurodegenerative diseases affecting humans and other mammals. Many genetic causes have been identified so far, including mutations of genes encoding proteins involved in mitochondrial dynamics. Recently, the "Turning calves syndrome", a novel sensorimotor polyneuropathy was described in the French Rouge-des-Prés cattle breed. In the present study, we determined that this hereditary disease resulted from a single nucleotide substitution in SLC25A46, a gene encoding a protein of the mitochondrial carrier family. This mutation caused an apparent damaging amino-acid substitution. To better understand the function of this protein, we knocked out the Slc25a46 gene in a mouse model. This alteration affected not only the nervous system but also altered general metabolism, resulting in premature mortality. Based on optic microscopy examination, electron microscopy and on biochemical, metabolic and proteomic analyses, we showed that the Slc25a46 disruption caused a fusion/fission imbalance and an abnormal mitochondrial architecture that disturbed mitochondrial metabolism. These data extended the range of phenotypes associated with Slc25a46 dysfunction. Moreover, this Slc25a46 knock-out mouse model should be useful to further elucidate the role of SLC25A46 in mitochondrial dynamics.

Published
2017
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8. Prion protein and Shadoo are involved in overlapping embryonic pathways and trophoblastic development.

Author

Bruno Passet, Rachel Young, Samira Makhzami, Marthe Vilotte, Florence Jaffrezic, Sophie Halliez, Stéphan Bouet, Sylvain Marthey, Manal Khalifé, Colette Kanellopoulos-Langevin, Vincent Béringue, Fabienne Le Provost, Hubert Laude, and Jean-Luc Vilotte

Subjects
Medicine, Science
Abstract

The potential requirement of either the Prion or Shadoo protein for early mouse embryogenesis was recently suggested. However, the current data did not allow to precise the developmental process that was affected in the absence of both proteins and that led to the observed early lethal phenotype. In the present study, using various Prnp transgenic mouse lines and lentiviral vectors expressing shRNAs that target the Shadoo-encoding mRNA, we further demonstrate the specific requirement of at least one of these two PrP-related proteins at early developmental stages. Histological analysis reveals developmental defect of the ectoplacental cone and important hemorrhage surrounding the Prnp-knockout-Sprn-knockdown E7.5 embryos. By restricting the RNA interference to the trophoblastic cell lineages, the observed lethal phenotype could be attributed to the sole role of these proteins in this trophectoderm-derived compartment. RNAseq analysis performed on early embryos of various Prnp and Sprn genotypes indicated that the simultaneous down-regulation of these two proteins affects cell-adhesion and inflammatory pathways as well as the expression of ectoplacental-specific genes. Overall, our data provide biological clues in favor of a crucial and complementary embryonic role of the prion protein family in Eutherians and emphasizes the need to further evaluate its implication in normal and pathological human placenta biology.

Published
2012
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9. Overexpression of miR-30b in the developing mouse mammary gland causes a lactation defect and delays involution.

Author

Sandrine Le Guillou, Nezha Sdassi, Johann Laubier, Bruno Passet, Marthe Vilotte, Johan Castille, Denis Laloë, Jacqueline Polyte, Stéphan Bouet, Florence Jaffrézic, Edmond-Paul Cribiu, Jean-Luc Vilotte, and Fabienne Le Provost

Subjects
Medicine, Science
Abstract

BACKGROUND: MicroRNA (miRNA) are negative regulators of gene expression, capable of exerting pronounced influences upon the translation and stability of mRNA. They are potential regulators of normal mammary gland development and of the maintenance of mammary epithelial progenitor cells. This study was undertaken to determine the role of miR-30b on the establishment of a functional mouse mammary gland. miR-30b is a member of the miR-30 family, composed of 6 miRNA that are highly conserved in vertebrates. It has been suggested to play a role in the differentiation of several cell types. METHODOLOGY/PRINCIPAL FINDINGS: The expression of miR-30b was found to be regulated during mammary gland development. Transgenic mice overexpressing miR-30b in mammary epithelial cells were used to investigate its role. During lactation, mammary histological analysis of the transgenic mice showed a reduction in the size of alveolar lumen, a defect of the lipid droplets and a growth defect of pups fed by transgenic females. Moreover some mammary epithelial differentiated structures persisted during involution, suggesting a delay in the process. The genes whose expression was affected by the overexpression of miR-30b were characterized by microarray analysis. CONCLUSION/SIGNIFICANCE: Our data suggests that miR-30b is important for the biology of the mammary gland and demonstrates that the deregulation of only one miRNA could affect lactation and involution.

Published
2012
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10. Transcriptomic analysis brings new insight into the biological role of the prion protein during mouse embryogenesis.

Author

Manal Khalifé, Rachel Young, Bruno Passet, Sophie Halliez, Marthe Vilotte, Florence Jaffrezic, Sylvain Marthey, Vincent Béringue, Daniel Vaiman, Fabienne Le Provost, Hubert Laude, and Jean-Luc Vilotte

Subjects
Medicine, Science
Abstract

The biological function of the Prion protein remains largely unknown but recent data revealed its implication in early zebrafish and mammalian embryogenesis. To gain further insight into its biological function, comparative transcriptomic analysis between FVB/N and FVB/N Prnp knockout mice was performed at early embryonic stages. RNAseq analysis revealed the differential expression of 73 and 263 genes at E6.5 and E7.5, respectively. The related metabolic pathways identified in this analysis partially overlap with those described in PrP1 and PrP2 knockdown zebrafish embryos and prion-infected mammalian brains and emphasize a potentially important role for the PrP family genes in early developmental processes.

Published
2011
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11. Co-invalidation of Prnp and Sprn in FVB/N mice affects reproductive performances and highlight complex biological relationship between PrP and Shadoo

Author

Anne Vaiman, Daniel Vaiman, Anne-Laure Gaillard, Marthe Vilotte, Samira Makhzami, Nathalie Daniel-Carlier, Amandine Duchesne, Pierre Calvel, Sandrine Floriot, Sophie Mouillet-Richard, Katayoun Moazami-Goudarzi, Vincent Béringue, Johan Castille, Jean-Luc Vilotte, Sandrine Truchet, Christian Beauvallet, Olivier Andreoletti, Bruno Passet, Génétique Animale et Biologie Intégrative (GABI), Université Paris-Saclay-AgroParisTech-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Virologie et Immunologie Moléculaires (VIM (UR 0892)), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), and INRAE Animal Genetic department project AAP.GA.2013

Subjects
Male, 0301 basic medicine, Protein family, [SDV]Life Sciences [q-bio], Biophysics, Embryonic Development, Mice, Transgenic, Nerve Tissue Proteins, Biology, GPI-Linked Proteins, Biochemistry, Prion Proteins, PRNP, Transcriptome, Mice, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Animals, Lactation, Molecular Biology, Gene, Mice, Knockout, Gene knockdown, [SDV.GEN]Life Sciences [q-bio]/Genetics, Reproduction, Embryogenesis, Cell Biology, Phenotype, Placentation, Cell biology, 030104 developmental biology, Animals, Newborn, 030220 oncology & carcinogenesis, Knockout mouse, Female, Genes, Lethal
Abstract

International audience; Shadoo and PrP belongs to the same protein family, whose biological function remains poorly understood. Previous experiments reported potential functional redundancies or antagonisms between these two proteins, depending on the tissue analysed. While knockdown experiments suggested the requirement of Shadoo in the absence of PrP during early mouse embryogenesis, knockout ones, on the contrary, highlighted little impact, if any, of the double-knockout of these two loci. In the present study, we reinvestigated the phenotype associated with the concomitant knockout of these two genes using newly produced FVB/N Sprn knockout mice. In this genetic background, the combined two genes & rsquo; knockout induces intra-uterine growth retardations, likely resulting from placental failures highlighted by transcriptomic analyses that revealed potential redundant or antagonist roles of these two proteins in different developmental-related pathways. It also induced an increased perinatal-lethality and ascertained the role of these two loci in the lactation process.

Published
2021

12. Targeting the Respiratory Syncytial Virus N 0 -P Complex with Constrained α-Helical Peptides in Cells and Mice

Author

Ronan Le Goffic, Vanessa Gaillard, Julie Rivière, Joelle Mettier, Charles-Adrien Richard, Origène Nyanguile, Nadege Gsponer, Thibaut Larcher, Brice Fenner, Marthe Vilotte, Marie Galloux, Jean-François Eléouët, Virologie et Immunologie Moléculaires (VIM (UR 0892)), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Haute École Spécialisée de Suisse Occidentale Valais-Wallis (HES-SO Valais-Wallis), Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Génétique Animale et Biologie Intégrative (GABI), Université Paris-Saclay-AgroParisTech-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), HES-SO University of Applied Sciences and Arts Western Switzerland RealTech Program 32324, and Ark Foundation 314-10

Subjects
viruses, respiratory syncytial virus, Mutant, Biology, stapled peptides, Virus, 03 medical and health sciences, N0-P complex, In vivo, antiviral agents, inhibitors, Pharmacology (medical), Mononegavirales, Polymerase, 030304 developmental biology, Pharmacology, 0303 health sciences, 030306 microbiology, Respiratory infection, RSV resistance mutants, biology.organism_classification, phosphoprotein, Virology, In vitro, 3. Good health, Infectious Diseases, Phosphoprotein, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein
Abstract

Respiratory syncytial virus (RSV) is the main cause of severe respiratory infection in young children worldwide, and no therapies have been approved for the treatment of RSV infection. Data from recent clinical trials of fusion or L polymerase inhibitors for the treatment of RSV-infected patients revealed the emergence of escape mutants, highlighting the need for the discovery of inhibitors with novel mechanisms of action. Here we describe stapled peptides derived from the N terminus of the phosphoprotein (P) that act as replication inhibitors. We demonstrate that these peptides inhibit RSV replication in vitro and in vivo by preventing the formation of the N0-P complex. The present strategy provides a novel means of targeting RSV replication with constrained macrocyclic peptides or small molecules and is broadly applicable to other viruses of the Mononegavirales order.

Published
2020

13. Targeting the Respiratory Syncytial Virus N

Author

Marie, Galloux, Nadège, Gsponer, Vanessa, Gaillard, Brice, Fenner, Thibaut, Larcher, Marthe, Vilotte, Julie, Rivière, Charles-Adrien, Richard, Jean-François, Eléouët, Ronan, Le Goffic, Joelle, Mettier, and Origène, Nyanguile

Subjects
Protein Conformation, alpha-Helical, Mice, Respiratory Syncytial Virus, Human, Animals, Humans, Respiratory Syncytial Virus Infections, Peptides, Phosphoproteins, Virus Replication, Antiviral Agents
Abstract

Respiratory syncytial virus (RSV) is the main cause of severe respiratory infection in young children worldwide, and no therapies have been approved for the treatment of RSV infection. Data from recent clinical trials of fusion or L polymerase inhibitors for the treatment of RSV-infected patients revealed the emergence of escape mutants, highlighting the need for the discovery of inhibitors with novel mechanisms of action. Here we describe stapled peptides derived from the N terminus of the phosphoprotein (P) that act as replication inhibitors. We demonstrate that these peptides inhibit RSV replication

Published
2020

14. Preeclampsia-Like Symptoms Induced in Mice by Fetoplacental Expression of STOX1 Are Reversed by Aspirin Treatment

Author

Daniel Vaiman, Marthe Vilotte, Jean-Luc Vilotte, Christophe Buffat, Nathalie Daniel, Céline Méhats, Johann Castille, Sandrine Barbaux, Alexandre Hertig, Ludivine Doridot, Véronique Baudrie, Umberto Simeoni, Françoise Mondon, Guy Germain, Aurélien Ducat, Fabienne Le Provost, Anne-Laure Bauchet, Bruno Passet, Michelle Breuiller-Fouché, Virginie Rigourd, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Génétique Animale et Biologie Intégrative ( GABI ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, Lactarium d'Ile de France, Institut de Puériculture et de Périnatalogie, Biologie du Développement et Reproduction ( BDR ), Institut National de la Recherche Agronomique ( INRA ), Service MIRCEN ( MIRCEN ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Paris-Centre de Recherche Cardiovasculaire, Hôpital Européen Georges Pompidou [APHP] ( HEGP ), UMR S702 Remodelage et Réparation du Tissu Rénal, Institut National de la Santé et de la Recherche Médicale, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes ( URMITE ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR48, INSB-INSB-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Biologie Moléculaire, Assistance Publique - Hôpitaux de Marseille ( APHM ), Service de Médecine Néonatale, INSERM, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Biologie du développement et reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Service MIRCEN (MIRCEN), Institut de Biologie François JACOB (JACOB), 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)-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)-Université Paris-Saclay, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École nationale vétérinaire - Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS), Vaiman, Daniel, ProdInra, Archive Ouverte, Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), AgroParisTech-Institut National de la Recherche Agronomique (INRA), Biologie du Développement et Reproduction (BDR), Institut National de la Recherche Agronomique (INRA), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Gestational hypertension, Placenta, souris, 030204 cardiovascular system & hematology, Kidney, Severity of Illness Index, Mice, 0302 clinical medicine, Pre-Eclampsia, Pregnancy, Medicine, [ SDV.SA ] Life Sciences [q-bio]/Agricultural sciences, [SDV.SA] Life Sciences [q-bio]/Agricultural sciences, 0303 health sciences, Anti-Inflammatory Agents, Non-Steroidal, Endoglin, Intracellular Signaling Peptides and Proteins, 3. Good health, Female, pré-éclampsie, Genetically modified mouse, medicine.medical_specialty, hypertension, Positional cloning, mouse model, preeclampsia, proteinuria, stox1, Mice, Transgenic, Article, Preeclampsia, 03 medical and health sciences, Internal medicine, Internal Medicine, Animals, Humans, Antihypertensive Agents, 030304 developmental biology, Fetus, Vascular Endothelial Growth Factor Receptor-1, Aspirin, business.industry, Choriocarcinoma, medicine.disease, Disease Models, Animal, Endocrinology, Carrier Proteins, business, Pregnancy disorder
Abstract

Preeclampsia (PE) is a common human-specific pregnancy disorder defined by hypertension and proteinuria during gestation and responsible for maternal and fetal morbimortality. STOX1 , encoding a transcription factor, was the first gene associated with PE as identified by positional cloning approaches. Its overexpression in choriocarcinoma cells mimics the transcriptional consequences of PE in the human placenta. Here, we created transgenic mouse strains overexpressing human STOX1 . Wild-type female mice crossed with transgenic male mice reproduce accurately the symptoms of severe PE: gestational hypertension, proteinuria, and elevated plasma levels of soluble fms-like tyrosine kinase 1 and soluble endoglin. Placental and kidney histology were altered. Symptoms were prevented or alleviated by aspirin treatment. STOX1-overexpressing mice constitute a unique model for studying PE, allow testing therapeutic approaches, and assessing the long-term effects of the preeclamptic syndrome.

Published
2013

15. Transmission du microARN miR-30b présent dans le lait de souris transgéniques chez le petit

Author

Sandrine Le Guillou, Johann Laubier, Johan Castille, Denis Laloë, Florence Jaffrezic, Stephan Bouet, Nezha Sdassi, Bruno Passet, Marthe Vilotte, Jean Luc Vilotte, Jacqueline Polyte, Fabienne Le Provost, Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, and Université Paris Saclay (COmUE)

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

National audience

Published
2016

16. Mutated but not deleted ovine PrPCN-terminal polybasic region strongly interferes with prion propagation in transgenic mice

Author

Johan Castille, Laetitia Herzog, Mohammed Moudjou, Samira Makhzami, Hubert Laude, Marthe Vilotte, Vincent Béringue, Olivier Andreoletti, Jean-Luc Vilotte, Manal Khalife, Didier Vilette, Fabienne Reine, Bruno Passet, Katayoun Moazami-Goudarzi, Sophie Paquet-Fifield, Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Unité de recherche Virologie et Immunologie Moléculaires (VIM), Institut National de la Recherche Agronomique (INRA), Interactions hôtes-agents pathogènes [Toulouse] (IHAP), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892))

Subjects
0301 basic medicine, Genetically modified mouse, Prions, Transgene, Bovine spongiform encephalopathy, animal diseases, [SDV]Life Sciences [q-bio], Immunology, Mutant, Mutation, Missense, Scrapie, Mice, Transgenic, Biology, Mouse Protein, medicine.disease_cause, Microbiology, Prion Diseases, 03 medical and health sciences, Virology, medicine, Animals, PrPC Proteins, Sequence Deletion, Mutation, Sheep, medicine.disease, Fungal prion, Cell biology, nervous system diseases, Disease Models, Animal, 030104 developmental biology, Insect Science, Mutant Proteins
Abstract

Mammalian prions are proteinaceous infectious agents composed of misfolded assemblies of the host-encoded, cellular prion protein (PrP). Physiologically, the N-terminal polybasic region of residues 23 to 31 of PrP has been shown to be involved in its endocytic trafficking and interactions with glycosaminoglycans or putative ectodomains of membrane-associated proteins. Several recent reports also describe this PrP region as important for the toxicity of mutant prion proteins and the efficiency of prion propagation, both in vitro and in vivo . The question remains as to whether the latter observations made with mouse PrP and mouse prions would be relevant to other PrP species/prion strain combinations given the dramatic impact on prion susceptibility of minimal amino acid substitutions and structural variations in PrP. Here, we report that transgenic mouse lines expressing ovine PrP with a deletion of residues 23 to 26 (KKRP) or mutated in this N-terminal region (KQHPH instead of KKRPK) exhibited a variable, strain-dependent susceptibility to prion infection with regard to the proportion of affected mice and disease tempo relative to findings in their wild-type counterparts. Deletion has no major effect on 127S scrapie prion pathogenesis, whereas mutation increased by almost 3-fold the survival time of the mice. Deletion marginally affected the incubation time of scrapie LA19K and ovine bovine spongiform encephalopathy (BSE) prions, whereas mutation caused apparent resistance to disease. IMPORTANCE Recent reports suggested that the N-terminal polybasic region of the prion protein could be a therapeutic target to prevent prion propagation or toxic signaling associated with more common neurodegenerative diseases such as Alzheimer's disease. Mutating or deleting this region in ovine PrP completes the data previously obtained with the mouse protein by identifying the key amino acid residues involved.

Published
2016

17. Short communication: Mouse mammary tumor virus driven α-lactalbumin expression effects on lactation and fertility of transgenic mice

Author

José Costa, Marthe Vilotte, L. Lefèvre, F. Le Provost, Jean-Luc Vilotte, Gaëlle Tilly, S. Le Guillou, and Bruno Passet

Subjects
Male, Genetically modified mouse, medicine.medical_specialty, Transgene, Mammary gland, Gene Expression, Mice, Transgenic, Ovary, Mice, 03 medical and health sciences, Mammary Glands, Animal, 0302 clinical medicine, Lactation, Internal medicine, Gene expression, Genetics, medicine, Animals, Involution (medicine), Promoter Regions, Genetic, 030304 developmental biology, 0303 health sciences, biology, Mouse mammary tumor virus, biology.organism_classification, Fertility, Endocrinology, medicine.anatomical_structure, Mammary Tumor Virus, Mouse, 030220 oncology & carcinogenesis, Lactalbumin, Female, Animal Science and Zoology, Food Science
Abstract

α-Lactalbumin (Alac) is one of the major milk proteins. Its gene expression is restricted to epithelial cells of the lactating mammary gland. The Alac interaction with a uridine 5'-diphosphate-galactosyltransferase induces lactose synthesis, a major osmotic regulator of milk secretion. Other functions attributed to this protein include induction of apoptosis and anti-inflammatory activities. To assess if forced expression of this gene during early gestation or involution could affect mammary physiology, an Alac-encoding minigene was expressed in transgenic mice under the transcriptional regulation of the mouse mammary tumor virus promoter. The mammary expression did not interfere with gestation, resulted in a slight increase in milk yield as indirectly assessed by the 11% increased growth rate of the pups reared by transgenic females compared with that of those reared by control mice, and induced a slight delay in the early involution process, as demonstrated by histological analyses. The use of the mouse mammary tumor virus promoter resulted in Alac expression in several nonmammary tissues, such as the brain, the testis, the ovary, and the uterus. Although it did not affect male reproductive performances, it induced a female subfertile phenotype, characterized by embryonic implantation failure in the transgenic female reproductive tract.

Published
2011

18. Poster Session PPo6: Functions and Cell Biology of PrP

Author

Manal Khalife, Jean-Luc Vilotte, Marie-Laure Martin-Magniette, Sead Chadi, Jean-Pierre Renou, Frédérique Bitton, Vincent Béringue, Hubert Laude, Lucas Lefevre, Sandrine Balzergue, Bruno Passet, Gaëlle Tilly, Sandrine Guillou, Marthe Vilotte, Fabienne Le Provost, Rachel Young, and Ludivine Soubigou-Taconnat

Subjects
Genetically modified mouse, 0303 health sciences, Microarray, Embryogenesis, Locus (genetics), Cell Biology, Biology, Biochemistry, Embryonic stem cell, Phenotype, PRNP, Cell biology, Transcriptome, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Infectious Diseases, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

The physiological function of the PrP remains largely elusive. Its invalidation does not affect mouse survival and induces subtle phenotypes. To potentially assess this conundrum, we first comparatively analyzed the adult brain transcriptome of wild-type mice with that of transgenic mice invalidated at this locus either at the zygotic (Zurich PrP0/0 mice) or adult stages (NFH-Cre-Lox mice). Only subtle differences could be evidenced in the adult brains following microarray and QPCR analyses. When performed at an early adult stage, neuronal Prnp disruption appeared to sequentially induce an oxidative stress response and a nervous system remodeling, but it involved a limited number of only slightly modified genes. In sharp contrast, analysis at early embryonic stages, 7.5 and 8.5 dpc, just after the suspected normal time set of the Prnp locus activation, led to a transient perturbation of the transcriptome involving a larger number of genes and pointing to potential pathways related to the PrP physiological function. Overall, our data suggests an early adaptation of the mouse to the potentially detrimental lack of PrP during embryogenesis while its presence is less influential or redundant at later developmental stages.

Published
2010

19. Submicroscopic Deletions at 13q32.1 Cause Congenital Microcoria

Author

Marthe Vilotte, Patrick Calvas, Arnold Munnich, Nicolas Chassaing, Olivier Roche, Akihiko Tawara, Josseline Kaplan, Antoine Guilloux, Alain Regnier, Jean-Yves Douet, Arturo Ramirez-Miranda, Christine Bole-Feysot, Elfride De Baere, Hannah Verdin, Bruno Passet, Yusuke Nakamura, Juan Carlos Zenteno, Hiroyuki Kondo, Masaru Iwai, Ken Yamamoto, Toshihiro Tanaka, Sylvie Gerber, Jean-Michel Rozet, Jean-Luc Vilotte, Wataru Kimura, Lucas Fares-Taie, Isabelle Raymond-Letron, Hugo Moisset, Sylvie Odent, 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 Occupational and Environmental Health [Kitakyushu] (UEOH), Instituto de Oftalmologia Fundacion Conde de la Valenciana AC, Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Center for Medical Genetics [Ghent], Ghent University Hospital, Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Kyushu University [Fukuoka], Ehime University [Matsuyama], Ehime University Graduate School of Medecine, Ehime Medical Center, Tokyo Medical and Dental University, Center for Integrative Medical Sciences (RIKEN), University of Chicago, Kimura Eye Clinic, Plateforme de génomique [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Universitaire de Toulouse, CHU Necker - Enfants Malades [AP-HP], This work was supported by grants from the Fédération des Aveugles de France (FAF) to LFT, Retina France to JMR and Geniris to JMR and PC, the Ministry of Education, Culture, Sport, Science and Technology of Japan Grant-in-aid N°20592067 to AT and the Conde de Valenciana Foundation patronage to ARM and JCZ., Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), University of Occupational and Environmental Health [Kitakyushu] ( UEOH ), Ecole Nationale Vétérinaire de Toulouse ( ENVT ), Institut National Polytechnique de Toulouse ( INPT ), Génétique Animale et Biologie Intégrative ( GABI ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, Center for Integrative Medical Sciences ( RIKEN ), Structure Fédérative de Recherche Necker ( SFR Necker - UMS 3633 / US24 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT), Kyushu University, Ehime University [Matsuyama, Japon], Laboratory for Cardiovascular Genomics and Informatics [Yokohama] (RIKEN IMS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universidad Nacional Autónoma de México (UNAM), AgroParisTech-Institut National de la Recherche Agronomique (INRA), Kagoshima University Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University [Japan] (TMDU), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), The University of Chicago Medicine [Chicago], Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Université Paris Descartes - Paris 5 (UPD5), Federation des Aveugles de France (FAF), Retina France, Geniris, Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) 20592067, Conde de Valenciana Foundation patronage, Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research (KAKENHI) 15K05577 221S0002, CARBILLET, Véronique, and Universidad Nacional Autónoma de México = National Autonomous University of Mexico (UNAM)

Subjects
MESH: Sequence Analysis, DNA, [SDV]Life Sciences [q-bio], MESH : Base Sequence, Chromosome Deletion, Chromosomes, Human, Pair 13/genetics, Comparative Genomic Hybridization, Gene Components, Genes, Dominant/genetics, Humans, Hydro-Lyases/genetics, Molecular Sequence Data, Mutation/genetics, Oligonucleotide Array Sequence Analysis, Pedigree, Pupil Disorders/congenital, Pupil Disorders/genetics, Pupil Disorders/pathology, Receptors, Cell Surface/genetics, Sequence Analysis, DNA, MESH: Receptors, Cell Surface / genetics, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Receptors, G-Protein-Coupled, MESH: Base Sequence, medicine.disease_cause, MESH: Pupil Disorders / pathology, Receptors, G-Protein-Coupled, 0302 clinical medicine, MESH: Genes, Dominant / genetics, Pupil Disorders, Myocyte, Genetics(clinical), MESH: Gene Components, 10. No inequality, MESH: Hydro-Lyases / genetics, MESH: Pupil Disorders / congenital, Genetics (clinical), Genes, Dominant, Genetics, 0303 health sciences, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Microcoria, MESH: Pupil Disorders / genetics, MESH: Pedigree, Receptors, Cell Surface, Biology, 03 medical and health sciences, Dysgenesis, MESH: Chromosome Deletion, Report, medicine, Gene, Hydro-Lyases, 030304 developmental biology, Sequence (medicine), [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, Chromosomes, Human, Pair 13, [ SDV ] Life Sciences [q-bio], MESH: Mutation / genetics, Breakpoint, Sequence Analysis, DNA, MESH: Chromosomes, Human, Pair 13 / genetics, Molecular biology, MESH: Comparative Genomic Hybridization, MESH: Oligonucleotide Array Sequence Analysis, 030221 ophthalmology & optometry, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Comparative genomic hybridization
Abstract

International audience; Congenital microcoria (MCOR) is a rare autosomal-dominant disorder characterized by inability of the iris to dilate owing to absence of dilator pupillae muscle. So far, a dozen MCOR-affected families have been reported worldwide. By using whole-genome oligonucleotide array CGH, we have identified deletions at 13q32.1 segregating with MCOR in six families originating from France, Japan, and Mexico. Breakpoint sequence analyses showed nonrecurrent deletions in 5/6 families. The deletions varied from 35 kbp to 80 kbp in size, but invariably encompassed or interrupted only two genes: TGDS encoding the TDP-glucose 4,6-dehydratase and GPR180 encoding the G protein-coupled receptor 180, also known as intimal thickness-related receptor (ITR). Unlike TGDS which has no known function in muscle cells, GPR180 is involved in the regulation of smooth muscle cell growth. The identification of a null GPR180 mutation segregating over two generations with iridocorneal angle dysgenesis, which can be regarded as a MCOR endophenotype, is consistent with the view that deletions of this gene, with or without the loss of elements regulating the expression of neighboring genes, are the cause of MCOR.

Published
2015

20. The prion protein family: a view from the placenta

Author

Jean Luc Vilotte, Johan Castille, Sophie Mouillet-Richard, Vincent Béringue, Hubert Laude, Samira Makzhami, Bruno Passet, Amandine Duchesne, Sophie Halliez, Daniel Vaiman, Marthe Vilotte, Katayoun Moazami-Goudarzi, Génétique Animale et Biologie Intégrative (GABI), AgroParisTech-Institut National de la Recherche Agronomique (INRA), Unité de recherche Virologie et Immunologie Moléculaires (VIM), Institut National de la Recherche Agronomique (INRA), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), ProdInra, Archive Ouverte, Université Paris Descartes - Paris 5 (UPD5)-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 Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA) - AgroParisTech, Toxicologie, Pharmacologie et Signalisation Cellulaire (U1124), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), and Institut Cochin (UM3 (UMR 8104 / U1016))

Subjects
placenta, [SDV]Life Sciences [q-bio], Review Article, Biology, Genome, prion, 03 medical and health sciences, Cell and Developmental Biology, 0302 clinical medicine, Placenta, medicine, mammals, shadoo, Prion protein, lcsh:QH301-705.5, Gene, development, 030304 developmental biology, Genetics, chemistry.chemical_classification, 0303 health sciences, Cell Biology, Embryonic stem cell, Phenotype, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, lcsh:Biology (General), chemistry, doppel, Prnp gene, Glycoprotein, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Based on its developmental pattern of expression, early studies suggested the implication of the mammalian Prion protein PrP, a glycosylphosphatidylinositol-anchored ubiquitously expressed and evolutionary conserved glycoprotein encoded by the [i]Prnp[/i] gene, in early embryogenesis. However, gene invalidation in several species did not result in obvious developmental abnormalities and it was only recently that it was associated in mice with intra-uterine growth retardation and placental dysfunction. A proposed explanation for this lack of easily detectable developmental-related phenotype is the existence in the genome of one or more gene (s) able to compensate for the absence of PrP. Indeed, two other members of the [i]Prnp[/i] gene family have been recently described, Doppel and Shadoo, and the consequences of their invalidation alongside that of PrP tested in mice. No embryonic defect was observed in mice depleted for Doppel and PrP. Interestingly, the co-invalidation of PrP and Shadoo in two independent studies led to apparently conflicting observations, with no apparent consequences in one report and the observation of a developmental defect of the ectoplacental cone that leads to early embryonic lethality in the other. This short review aims at summarizing these recent, apparently conflicting data highlighting the related biological questions and associated implications in terms of animal and human health.

Published
2014

21. Prion Protein-Encoding Genes

Author

Sandrine Balzergue, Rachel Young, Hubert Laude, Marthe Vilotte, Coralie Peyre, Jean-Pierre Renou, Marie-Laure Martin-Magniette, Jean-Luc Vilotte, Fabienne Le Provost, Sead Chadi, Gaëlle Tilly, Bruno Passet, Ludivine Soubigou-Taconnat, Sandrine Guillou, and Frédérique Bitton

Subjects
Genetics, Encoding (semiotics), Prion protein, Biology, Gene, Fungal prion
Published
2013

22. Targeted knock-down of cellular prion protein expression in myelinating Schwann cells does not alter mouse prion pathogenesis

Author

Giovanna R. Mallucci, Jean Luc Vilotte, Hubert Laude, Emilie Jaumain, Christelle Langevin, Sophie Halliez, Nathalie Chesnais, Vincent Béringue, Marthe Vilotte, Unité de recherche Virologie et Immunologie Moléculaires (VIM), Institut National de la Recherche Agronomique (INRA), Génétique Animale et Biologie Intégrative (GABI), AgroParisTech-Institut National de la Recherche Agronomique (INRA), Toxicology Unit, Medical Research Council, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), and Institut National de la Recherche Agronomique (INRA)-AgroParisTech

Subjects
[SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Male, Transgene, animal diseases, Central nervous system, Mice, Transgenic, Biology, Prion Diseases, Pathogenesis, 03 medical and health sciences, Mice, 0302 clinical medicine, Virology, medicine, Animals, Humans, PrPC Proteins, Prion protein, Myelin Sheath, 030304 developmental biology, 0303 health sciences, Neurodegeneration, Gene targeting, Brain, medicine.disease, nervous system diseases, medicine.anatomical_structure, nervous system, Peripheral nervous system, Gene Knockdown Techniques, Gene Targeting, Female, Schwann Cells, 030217 neurology & neurosurgery
Abstract

In naturally acquired transmissible spongiform encephalopathies, the pathogenic agents or prions spread from the sites of initial peripheral uptake or replication to the brain where they cause progressive and fatal neurodegeneration. Routing via the peripheral nervous system is considered to be one of the main pathways to the central nervous system. Replication of prions in Schwann cells is viewed as a potentially important mechanism for efficient prion spread along nerves. Here we used a Cre-loxP mouse transgenetic approach to disrupt host-encoded prion protein (PrPC) specifically in myelinating Schwann cells. Despite the use of infection routes targeting highly myelinated nerves, there was no alteration in mouse prion pathogenesis, suggesting that conversion-dependent, centripetal spread of prions does not crucially rely on PrPC expressed by myelinating Schwann cells.

Published
2013

23. STOX1 overexpression in mice induces severe preeclampsia-like symptoms prevented by aspirin at low doses

Author

Céline Méhats, Jean-Luc Vilotte, Françoise Mondon, Sandrine Barbaux, Ludivine Doridot, Bruno Passet, Sébastien Jacques, Johann Castille, Michelle Breuiller-Fouché, Daniel Vaiman, Marthe Vilotte, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Institut Cochin (UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA) - AgroParisTech, and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
medicine.medical_specialty, Aspirin, 030219 obstetrics & reproductive medicine, business.industry, [SDV]Life Sciences [q-bio], Immunology, Low dose, Obstetrics and Gynecology, medicine.disease, Severe preeclampsia, 3. Good health, Preeclampsia, [SDV] Life Sciences [q-bio], preeclampsia, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Reproductive Medicine, Internal medicine, medicine, Immunology and Allergy, 030212 general & internal medicine, business, medicine.drug
Abstract

absent

Published
2012

24. Prion protein and shadoo are involved in overlapping embryonic pathways and trophoblastic development

Author

Colette Kanellopoulos-Langevin, Samira Makhzami, Vincent Béringue, Jean Luc Vilotte, Florence Jaffrézic, Sylvain Marthey, Manal Khalife, Marthe Vilotte, Bruno Passet, Stephan Bouet, Hubert Laude, Sophie Halliez, Fabienne Le Provost, Rachel Young, Vilotte, Jean Luc, Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Unité de recherche Virologie et Immunologie Moléculaires (VIM), Institut National de la Recherche Agronomique (INRA), Laboratory of Inflammation, Gestation and Autoimmunity, J. Monod Institute, UMR 7592, Centre National de la Recherche Scientifique (CNRS), This work was supported by the ANR-09-BLAN-0015-01 and by the Institut National de la Recherche Agronomique AIP BioRessources PRIFASTEM., and Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892))

Subjects
[SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Embryology, Cellular differentiation, Developmental Signaling, Mice, 0302 clinical medicine, RNA interference, Gene expression, Molecular Cell Biology, Genetics, Regulation of gene expression, Mice, Knockout, 0303 health sciences, cellular prion, Multidisciplinary, lacking, Gene Expression Regulation, Developmental, Signaling in Selected Disciplines, Phenotype, Trophoblasts, Medicine, RNA Interference, Genetic Engineering, prion protein, expression, gene, inflammation, Research Article, Biotechnology, Signal Transduction, Genetically modified mouse, Prions, Science, Embryonic Development, Nerve Tissue Proteins, Biology, GPI-Linked Proteins, PRNP, 03 medical and health sciences, Animals, RNA, Messenger, Gene, 030304 developmental biology, Molecular Development, Gene Function, Animal Genetics, 030217 neurology & neurosurgery, Transgenics, Developmental Biology
Abstract

The potential requirement of either the Prion or Shadoo protein for early mouse embryogenesis was recently suggested. However, the current data did not allow to precise the developmental process that was affected in the absence of both proteins and that led to the observed early lethal phenotype. In the present study, using various Prnp transgenic mouse lines and lentiviral vectors expressing shRNAs that target the Shadoo-encoding mRNA, we further demonstrate the specific requirement of at least one of these two PrP-related proteins at early developmental stages. Histological analysis reveals developmental defect of the ectoplacental cone and important hemorrhage surrounding the Prnp-knockout-Sprn-knockdown E7.5 embryos. By restricting the RNA interference to the trophoblastic cell lineages, the observed lethal phenotype could be attributed to the sole role of these proteins in this trophectoderm-derived compartment. RNAseq analysis performed on early embryos of various Prnp and Sprn genotypes indicated that the simultaneous down-regulation of these two proteins affects cell-adhesion and inflammatory pathways as well as the expression of ectoplacental-specific genes. Overall, our data provide biological clues in favor of a crucial and complementary embryonic role of the prion protein family in Eutherians and emphasizes the need to further evaluate its implication in normal and pathological human placenta biology.

Published
2012

25. Generation of Sprn-regulated reporter mice reveals gonadic spatial expression of the prion-like protein Shadoo in mice

Author

Gaëlle Tilly, Jean Luc Vilotte, Sandrine Guillou, Rachel Young, Vincent Béringue, Hubert Laude, Johan Castille, Bruno Passet, Marthe Vilotte, Fabienne Le Provost, Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Unité de recherche Virologie et Immunologie Moléculaires (VIM), Institut National de la Recherche Agronomique (INRA), Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), and AgroParisTech-Institut National de la Recherche Agronomique (INRA)

Subjects
Genetically modified mouse, [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Prions, Transgene, Green Fluorescent Proteins, Biophysics, lac operon, Gene Expression, Mice, Transgenic, Nerve Tissue Proteins, Biology, GPI-Linked Proteins, Biochemistry, 03 medical and health sciences, Exon, Mice, 0302 clinical medicine, Genes, Reporter, Gene expression, gonadic expression, Animals, Tissue Distribution, transgenic reporter mice, shadoo, Gonads, Molecular Biology, Gene, 030304 developmental biology, 0303 health sciences, Reporter gene, Intron, fertility and reproduction, Cell Biology, paralogue of prion protein, beta-Galactosidase, Molecular biology, lacz, 030217 neurology & neurosurgery
Abstract

The protein Shadoo (Sho) is a paralogue of prion protein, and encoded by the gene Sprn. Like prion protein it is primarily expressed in central nervous system, and has been shown to have a similar expression pattern in certain regions of the brain. We have generated reporter mice carrying a transgene encompassing the Sprn promoter, exon 1, intron 1 and the 5′-end of exon 2 driving expression of either the LacZ or GFP reporter gene to study the expression profile of Shadoo in mice. Expression of the reporter genes was analysed in brains of these transgenic mice and was shown to mimic that of the endogenous gene expression, previously described by Watts et al. [1]. Consequently, the Sprn-LacZ mice were used to study the spatial expression of Sho in other tissues of the adult mouse. Several tissues were collected and stained for β-gal activity, including the thymus, heart, lung, liver, kidney, spleen, intestine, muscle, and gonads. From this array of tissues, the transgene was consistently expressed only in specific cell types of the testicle and ovary, suggesting a role for Shadoo in fertility and reproduction. These mice may serve as a useful tool in deciphering the regulation of the prion-like gene Sprn and thus, indirectly, of the Shadoo protein.

Published
2011

26. Transcriptomic Analysis Brings New Insight into the Biological Role of the Prion Protein during Mouse Embryogenesis

Author

Rachel Young, Vincent Béringue, Bruno Passet, Florence Jaffrézic, Daniel Vaiman, Jean Luc Vilotte, Manal Khalife, Marthe Vilotte, Sylvain Marthey, Fabienne Le Provost, Sophie Halliez, Hubert Laude, Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ProdInra, Archive Ouverte, Vilotte, Jean Luc, AgroParisTech-Institut National de la Recherche Agronomique (INRA), Unité de recherche Virologie et Immunologie Moléculaires (VIM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Institut National de la Recherche Agronomique (INRA) - AgroParisTech, and Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Embryology, Embryo, Nonmammalian, Mouse, animal diseases, Gene regulatory network, prion protein, prp, zebrafish, mammalian, embryogenesis, Transcriptomes, Prion Diseases, Transcriptome, Mice, 0302 clinical medicine, Protein Isoforms, Gene Regulatory Networks, Zebrafish, Regulation of gene expression, Genetics, Mice, Knockout, 0303 health sciences, Gene knockdown, [SDV.SA] Life Sciences [q-bio]/Agricultural sciences, Multidisciplinary, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Regulation, Developmental, Genomics, Animal Models, Immunohistochemistry, Infectious Diseases, Gene Knockdown Techniques, Knockout mouse, Medicine, Research Article, Histology, Prions, Science, Embryonic Development, Biology, PRNP, 03 medical and health sciences, Model Organisms, Genome Analysis Tools, Animals, Gene Networks, 030304 developmental biology, Gene Expression Profiling, Molecular Development, Zebrafish Proteins, biology.organism_classification, Embryo, Mammalian, Gene expression profiling, Gene Function, Genome Expression Analysis, Animal Genetics, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Chantier qualité GA; The biological function of the Prion protein remains largely unknown but recent data revealed its implication in early zebrafish and mammalian embryogenesis. To gain further insight into its biological function, comparative transcriptomic analysis between FVB/N and FVB/N Prnp knockout mice was performed at early embryonic stages. RNAseq analysis revealed the differential expression of 73 and 263 genes at E6.5 and E7.5, respectively. The related metabolic pathways identified in this analysis partially overlap with those described in PrP1 and PrP2 knockdown zebrafish embryos and prion-infected mammalian brains and emphasize a potentially important role for the PrP family genes in early developmental processes.

Published
2011

27. Expression of the prion-like protein Shadoo in the developing mouse embryo

Author

Fabienne Le Provost, Jean Luc Vilotte, Sandrine Guillou, Vincent Béringue, Bruno Passet, Johan Castille, Rachel Young, Marthe Vilotte, Stephan Bouet, Jacqueline Polyte, Hubert Laude, Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), This work was supported by the ANR-09-BLAN-0015-01., AgroParisTech-Institut National de la Recherche Agronomique (INRA), and Unité de recherche Virologie et Immunologie Moléculaires (VIM)

Subjects
[SDV.SA]Life Sciences [q-bio]/Agricultural sciences, specific embryonic cell lineage, Prions, Transgene, Biophysics, Mice, Transgenic, Nerve Tissue Proteins, Biology, GPI-Linked Proteins, Prion Proteins, mouse embryo development, 03 medical and health sciences, Mice, 0302 clinical medicine, shadoo protein, Gene Knockdown Techniques, Animals, biochemistry, molecular biology, Cell Lineage, Beta-galactosidase, Transgenes, extraembryonic tissue, Gene, 030304 developmental biology, 0303 health sciences, Gene knockdown, developmental expression, Embryo, Cell Biology, Embryo, Mammalian, beta-Galactosidase, Phenotype, Embryonic stem cell, Molecular biology, biophysic, biology.protein, 030217 neurology & neurosurgery
Abstract

The prion-like protein Shadoo has been suggested to compensate for the lack of PrP in Prnp-knockout mice, explaining their lack of extreme phenotype. In adult mice, both PrP and Shadoo have shown overlapping expression patterns and shared functions [1] . Their expression in the mouse embryo has also been suggested to be complementary, as invalidation of both genes results in embryonic lethality [2] . The developmental expression profile of PrP has been described from post-implantation stages up until birth [3] , [4] , [5] . However the spatial expression pattern of Shadoo in the developing mouse embryo is not known. We previously described the expression profile of the prion-like protein Shadoo in adult mice using Sprn reporter mice (Sprn-GFP and Sprn-LacZ). Here we used these mice to describe the developmental expression of Shadoo between 10.5 and 14.5 dpc. The observed pattern in specific embryonic cell lineages and in extra-embryonic tissues is consistent with the previously reported phenotype resulting from its knockdown.

Published
2011

28. Brain transcriptional stability upon prion protein-encoding gene invalidation in zygotic or adult mouse

Author

Jean-Pierre Renou, Sead Chadi, Marthe Vilotte, Vincent Béringue, Frédérique Bitton, Marie-Laure Martin-Magniette, Sandrine Guillou, Ludivine Soubigou-Taconnat, Sandrine Balzergue, Gaëlle Tilly, Coralie Peyre, Bruno Passet, Jean-Luc Vilotte, Rachel Young, Hubert Laude, Fabienne Le Provost, Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Unité de recherche en génomique végétale (URGV), Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Recherche Agronomique (INRA), Mathématiques et Informatique Appliquées (MIA-Paris), AgroParisTech-Institut National de la Recherche Agronomique (INRA), Infectiologie Expérimentale des Rongeurs et Poissons (IERP), Institut National de la Recherche Agronomique (INRA), Unité de recherche Virologie et Immunologie Moléculaires (VIM), Institut National de la Recherche Agronomique (INRA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), and Vilotte, Jean Luc

Subjects
Male, Genetically modified mouse, Aging, Transcription, Genetic, lcsh:QH426-470, Prions, Zygote, lcsh:Biotechnology, [SDV]Life Sciences [q-bio], Population, Biology, PRNP, Transcriptome, prion, Gene Knockout Techniques, Mice, 03 medical and health sciences, 0302 clinical medicine, lcsh:TP248.13-248.65, Genetics, Animals, Gene Silencing, education, gene, Gene, mouse, 030304 developmental biology, Neurons, 0303 health sciences, education.field_of_study, Microarray analysis techniques, Gene Expression Profiling, Brain, transcriptomic, infection, Gene expression profiling, lcsh:Genetics, Genetic Loci, Female, 030217 neurology & neurosurgery, Research Article, Biotechnology
Abstract

Background The physiological function of the prion protein remains largely elusive while its key role in prion infection has been expansively documented. To potentially assess this conundrum, we performed a comparative transcriptomic analysis of the brain of wild-type mice with that of transgenic mice invalidated at this locus either at the zygotic or at the adult stages. Results Only subtle transcriptomic differences resulting from the Prnp knockout could be evidenced, beside Prnp itself, in the analyzed adult brains following microarray analysis of 24 109 mouse genes and QPCR assessment of some of the putatively marginally modulated loci. When performed at the adult stage, neuronal Prnp disruption appeared to sequentially induce a response to an oxidative stress and a remodeling of the nervous system. However, these events involved only a limited number of genes, expression levels of which were only slightly modified and not always confirmed by RT-qPCR. If not, the qPCR obtained data suggested even less pronounced differences. Conclusions These results suggest that the physiological function of PrP is redundant at the adult stage or important for only a small subset of the brain cell population under classical breeding conditions. Following its early reported embryonic developmental regulation, this lack of response could also imply that PrP has a more detrimental role during mouse embryogenesis and that potential transient compensatory mechanisms have to be searched for at the time this locus becomes transcriptionally activated.

Published
2010

29. Goat RSPO1 over-expression rescues sex-reversal in Rspo1-knockout XX mice but does not perturb testis differentiation in XY or sex-reversed XX mice

Author

Johann Laubier, Bruno Passet, Marie-Christine Chaboissier, Maëlle Pannetier, Lauriane Renault, Sead Chadi, Anne-Amandine Chassot, Fatemeh Montazer-Torbati, Fabienne Le Provost, José Costa, Marthe Vilotte, Jean-Luc Vilotte, Aurélie Auguste, Laurine Buscara, Eric Pailhoux, Unité de recherche Génétique Biochimique et Cytogénétique (LGBC), Institut National de la Recherche Agronomique (INRA), Biologie du développement et reproduction (BDR), Centre National de la Recherche Scientifique (CNRS)-École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique du développement normal et pathologique, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was partially supported by the ANR-06, GenAnimal TEGOD., ProdInra, Migration, École nationale vétérinaire - Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), and Université Nice Sophia Antipolis (1965 - 2019) (UNS)

Subjects
Male, Chromosomes, Artificial, Bacterial, X Chromosome, Transgene, [SDV]Life Sciences [q-bio], Disorders of Sex Development, sex determination, Biology, [INFO] Computer Science [cs], Y chromosome, transgenesis, Animals, Genetically Modified, 03 medical and health sciences, Mice, 0302 clinical medicine, Y Chromosome, Testis, Genetics, Animals, Humans, [INFO]Computer Science [cs], Transgenes, RSPO1, X chromosome, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Sexual differentiation, Male Phenotype, Goats, SOXB1 Transcription Factors, Cell Differentiation, Sex reversal, Phenotype, Molecular biology, [SDV] Life Sciences [q-bio], Fertility, r-spondin1, Animal Science and Zoology, Female, Thrombospondins, Agronomy and Crop Science, 030217 neurology & neurosurgery, bac, Biotechnology
Abstract

Chantier qualité GA; International audience; RSPO1 is a newly discovered gene involved in sex differentiation. Two goat BAC clones encompassing the RSPO1 gene (gRSPO1) were injected into mouse oocytes and several transgenic lines derived. Both clones induced gRSPO1 over-expression in various tissues, including male and female gonads, with no obvious phenotype and normal sex-ratios. Introgression of the gRSPO1 transgene into a mouse RSPO1 knockout genotype resulted in the rescue of the fertility and the disappearance of the masculinized gonadic features of the females, demonstrating the functionality of the goat protein in a mouse context. On the contrary, over-expression of gRSPO1 within a mSRY or a gSRY-XX genotypes did not interfere with the SRY-induced male phenotype.

Published
2009

30. The prion or the related Shadoo protein is required for early mouse embryogenesis

Author

Vincent Béringue, Bruno Passet, Rachel Young, Hubert Laude, Edmond P. Cribiu, Fabienne Le Provost, Jean-Luc Vilotte, Marthe Vilotte, Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Unité de recherche Virologie et Immunologie Moléculaires (VIM), Institut National de la Recherche Agronomique (INRA), R.Y. is a post-doctoral scientist supported by the French Ministry of Research. This work was partially supported by the ANR-09-BLAN-0015-01., and Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892))

Subjects
Protein family, Prions, animal diseases, [SDV]Life Sciences [q-bio], Biophysics, Down-Regulation, Embryonic Development, embryo, Nerve Tissue Proteins, Biology, GPI-Linked Proteins, Biochemistry, transgenesis, prion, rna interference, 03 medical and health sciences, Mice, 0302 clinical medicine, Downregulation and upregulation, Structural Biology, RNA interference, Genetics, Gene Knockdown Techniques, Animals, shadoo, Molecular Biology, Gene, mouse, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Gene knockdown, Lentivirus, Embryo, Cell Biology, Phenotype, nervous system diseases, Genes, Lethal, 030217 neurology & neurosurgery
Abstract

The prion protein PrP has a key role in transmissible spongiform encephalopathies but its biological function remains largely unknown. Recently, a related protein, Shadoo, was discovered. Its biological properties and brain distribution partially overlap that of PrP. We report that the Shadoo-encoding gene knockdown in PrP-knockout mouse embryos results in a lethal phenotype, occurring between E8 and E11, not observed on the wild-type genetic background. It reveals that these two proteins play a shared, crucial role in mammalian embryogenesis, explaining the lack of severe phenotype in PrP-knockout mammals, an appreciable step towards deciphering the biological role of this protein family.

Published
2009

31. Prnp knockdown in transgenic mice using RNA interference

Author

Jean-Luc Vilotte, Coralie Peyre, Micaela Gallozzi, Philippe Tixador, Eric Pailhoux, Fabienne Le Provost, Gaëlle Tilly, Caroline Morgenthaler, Hubert Laude, Nathalie Daniel-Carlier, Laetitia Herzog, Annick Le Dur, Vincent Béringue, Jérôme Chapuis, Marthe Vilotte, José Costa, Bruno Passet, Unité de recherche Génétique Biochimique et Cytogénétique (LGBC), Institut National de la Recherche Agronomique (INRA), Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Unité animalerie rongeurs, Biologie du développement et reproduction (BDR), and Centre National de la Recherche Scientifique (CNRS)-École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)

Subjects
Genetically modified mouse, Prions, Transgene, Genetic Vectors, Down-Regulation, Mice, Transgenic, Biology, Prion Proteins, PRNP, Cell Line, 03 medical and health sciences, Mice, 0302 clinical medicine, RNA interference, microRNA, Genetics, Gene silencing, Animals, PrPC Proteins, 030304 developmental biology, DNA Primers, 0303 health sciences, Messenger RNA, Gene knockdown, [SDV.GEN]Life Sciences [q-bio]/Genetics, Base Sequence, Molecular biology, MicroRNAs, Animal Science and Zoology, RNA Interference, Agronomy and Crop Science, 030217 neurology & neurosurgery, Biotechnology
Abstract

International audience; RNA interference has become a widely used approach to perform gene knockdown experiments in cell cultures and more recently transgenic animals. A designed miRNA targeting the prion protein mRNA was built and expressed using the human PRNP promoter. Its efficiency was confirmed in transfected cells and it was used to generate several transgenic mouse lines. Although expressed at low levels, it was found to downregulate the endogenous mouse Prnp gene expression to an extent that appears to be directly related with the transgene expression level and that could reach up to 80% inhibition. This result highlights the potential and limitations of the RNA interference approach when applied to disease resistance.

Published
2008

32. Overexpression of miR-30b in the Developing Mouse Mammary Gland Causes a Lactation Defect and Delays Involution

Author

Stephan Bouet, Johan Castille, Nezha Sdassi, Jean-Luc Vilotte, Bruno Passet, Edmond-Paul Cribiu, Sandrine Guillou, Johann Laubier, Denis Laloë, Florence Jaffrézic, Marthe Vilotte, Jacqueline Polyte, Fabienne Le Provost, Le Provost, Fabienne, Génétique Animale et Biologie Intégrative (GABI), and Institut National de la Recherche Agronomique (INRA)-AgroParisTech

Subjects
[SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Mouse, Cellular differentiation, Mammary gland, Gene Identification and Analysis, lcsh:Medicine, Polymerase Chain Reaction, Mice, 0302 clinical medicine, Lactation, Molecular Cell Biology, Gene expression, lcsh:Science, Oligonucleotide Array Sequence Analysis, 0303 health sciences, Multidisciplinary, Cell Differentiation, Genomics, Animal Models, Cell biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, Research Article, Genetically modified mouse, medicine.medical_specialty, Transgene, Mice, Transgenic, Biology, Molecular Genetics, 03 medical and health sciences, Mammary Glands, Animal, Model Organisms, Internal medicine, Genetics, medicine, Animals, Gene Regulation, Involution (medicine), Progenitor cell, DNA Primers, 030304 developmental biology, Base Sequence, lcsh:R, MicroRNAs, Endocrinology, RNA processing, lcsh:Q, Gene Function, Genome Expression Analysis, Animal Genetics
Abstract

Chantier qualité GA; Background: MicroRNA (miRNA) are negative regulators of gene expression, capable of exerting pronounced influences upon the translation and stability of mRNA. They are potential regulators of normal mammary gland development and of the maintenance of mammary epithelial progenitor cells. This study was undertaken to determine the role of miR-30b on the establishment of a functional mouse mammary gland. miR-30b is a member of the miR-30 family, composed of 6 miRNA that are highly conserved in vertebrates. It has been suggested to play a role in the differentiation of several cell types.[br/] Methodology/Principal Findings: The expression of miR-30b was found to be regulated during mammary gland development. Transgenic mice overexpressing miR-30b in mammary epithelial cells were used to investigate its role. During lactation, mammary histological analysis of the transgenic mice showed a reduction in the size of alveolar lumen, a defect of the lipid droplets and a growth defect of pups fed by transgenic females. Moreover some mammary epithelial differentiated structures persisted during involution, suggesting a delay in the process. The genes whose expression was affected by the overexpression of miR-30b were characterized by microarray analysis.[br/] Conclusion/Significance: Our data suggests that miR-30b is important for the biology of the mammary gland and demonstrates that the deregulation of only one miRNA could affect lactation and involution.

Published
2012

33. Goat RSPO1 over-expression rescues sex-reversal in Rspo1-knockout XX mice but does not perturb testis differentiation in XY or sex-reversed XX mice.

Author

Laurine Buscara, Fatemeh Montazer-Torbati, Sead Chadi, Aurélie Auguste, Johann Laubier, Anne-Amandine Chassot, Lauriane Renault, Bruno Passet, José Costa, Maëlle Pannetier, Marthe Vilotte, Marie-Christine Chaboissier, Jean-Luc Vilotte, Eric Pailhoux, and Fabienne Le Provost

Abstract

Abstract   RSPO1 is a newly discovered gene involved in sex differentiation. Two goat BAC clones encompassing the RSPO1 gene (gRSPO1) were injected into mouse oocytes and several transgenic lines derived. Both clones induced gRSPO1 over-expression in various tissues, including male and female gonads, with no obvious phenotype and normal sex-ratios. Introgression of the gRSPO1 transgene into a mouse RSPO1 knockout genotype resulted in the rescue of the fertility and the disappearance of the masculinized gonadic features of the females, demonstrating the functionality of the goat protein in a mouse context. On the contrary, over-expression of gRSPO1 within a mSRY or a gSRY-XX genotypes did not interfere with the SRY-induced male phenotype. [ABSTRACT FROM AUTHOR]

Published
2009
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34. Prnp knockdown in transgenic mice using RNA interference.

Author

Micaela Gallozzi, Jérome Chapuis, Fabienne Le Provost, Annick Le Dur, Caroline Morgenthaler, Coralie Peyre, Nathalie Daniel-Carlier, Eric Pailhoux, Marthe Vilotte, Bruno Passet, Laetitia Herzog, Vincent Beringue, José Costa, Philippe Tixador, Gaëlle Tilly, Hubert Laude, and Jean-Luc Vilotte

Abstract

Abstract  RNA interference has become a widely used approach to perform gene knockdown experiments in cell cultures and more recently transgenic animals. A designed miRNA targeting the prion protein mRNA was built and expressed using the human PRNP promoter. Its efficiency was confirmed in transfected cells and it was used to generate several transgenic mouse lines. Although expressed at low levels, it was found to downregulate the endogenous mouse Prnp gene expression to an extent that appears to be directly related with the transgene expression level and that could reach up to 80% inhibition. This result highlights the potential and limitations of the RNA interference approach when applied to disease resistance. [ABSTRACT FROM AUTHOR]

Published
2008
Full Text
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