Pathophysiology of vitamin A signaling pathways

Pathophysiology of vitamin A signaling pathways

Retinoic acid (ATRA), the active metabolite of vitamin A, is produced locally in its target tissues. It is essential for development and reproduction. Its pharmaceutical derivatives are therapeutic tools with a promising potential. Our project is to decipher, step by step, the ATRA-dependent processes involved in the differentiation of cells in vivo, focusing on mouse germ cells (GC), at the origin of gametes, as a model system.

The chronology of gametogenesis in mammals varies according to the sex. Most females are born with a definite reserve of germ cells (GC), the number of which determines fertility. In males, fertility relies on a permanent balance between self-renewal and differentiation of GC. In both sexes, undifferentiated precursors divide to increase the GC population. Later, GC enter into meiosis, achieving genetic recombination and halving the number of chromosomes required for the production of haploid gametes. Genetic and pharmacological studies in mice have revealed that ATRA and its nuclear receptors (RAR) are major players in gametogenesis. Our project aims to decipher, step by step, the ATRA-dependent processes required for the differentiation of GC in vivo, starting from stem cells capable of self-renewal to gametes that are able to fertilize, including the meiotic step through which chromosomes are intermingled at each generation to ensure the genetic diversity of individuals. To this end, we possess a collection of mice, unique worldwide in its diversity, in which one or several players in the ATRA signalling pathway are knocked out, as well as the scientific expertise and know-how to characterize the molecular and tissue abnormalities.

Overall, our project is expected to allow advances towards a better understanding of human gonadal pathologies (e.g., premature ovarian failure, sperm production defects) and to develop retinoid therapies (using agonists or antagonists) for infertile patients. The possibility to transiently disrupt ATRA signalling also represents a promising strategy to develop male contraceptives, provided that the mechanism of ATRA functioning is completely deciphered in order to prevent side effects.
Beyond gametogenesis, our project will help to understand how ATRA controls the differentiation of stem cells, normal or cancerous.



Deconstructing and reconstructing embryos

Choose: anonymous connexion

Password: ontogenesis


Collaborations and networks

Gérard BENOIT, ORCID ID Laboratoire de Biologie et Modélisation de la Cellule (LBMC, CNRS UMR 5239), Ecole Normale Supérieur, Lyon, France. Team Systems Biology of Decision Making, Axis 2 LITREA: Deciphering nuclear receptor biological function in differentiating mouse pluripotent embryonic cells



Marie-Christine CHABOISSIER, ORCID ID Institute Biologie Valrose (iBV, INSERM U1091, CNRS UMR 7277), Nice-Côte d’Azur University, Nice, France. Team Sex determination in mice



Frédéric CHALMEL, ORCID ID Research Institute for Environmental and Occupational Health (IRSET, INSERM UMR 1085), Rennes, France. Team Physiology and Physiopathology of the Uro-Genital Tract, Head of Axis 4 : Gonad differentiation and physiology



Gregg DUESTER, ORCID ID Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute (SBP), Development, Aging and Regeneration Program, La Jolla, California, USA. Team leader



Pierre GERMAIN, ORCID ID Centre de Biologie Structurale (CBS, CNRS UMR 5048, INSERM U 1054), Montpellier, France. Team Nuclear Receptors as Integrators of Endogenous and Environmental Signals




Gabriel LIVERA, ORCID ID Institute of cellular and molecular radiobiology (IRCM CEA), Genetic Stability, Stem Cells and Radiation (UMR SGCSR), Fontenay aux Roses, France. Team Development of the Gonads.




Serge NEF, ORCID ID University of Genève, Department of Genetic Medicine and Development, Geneva, Swiss. Team Molecular and Developmental Biology of Sexual Development




Eric PAILHOUX, ORCID ID Biology of Reproduction, Environnement, Epigenetics, and Development (BREED, INRAE UMR 1198), Jouy-en-Josas, France. Team Gonad Differentiation and its Perturbations




Bertrand SERAPHIN, ORCID ID Institute of Genetics, Molecular and Cellular Biology (IGBMC, CNRS UMR7104, INSERM U1258), Department of Functional Genomics and Cancer, Illkirch, France. Team Protein networks and complexes regulating eukaryotic mRNA decay  



Michael WEBER, ORCID ID Biotechnology and Cell Signalling (BSC, CNRS UMR 7242), ESBS, Illkirch, France. Team Epigenetic regulation of cell identity

Funding and partners

  • ANR 2021 (PRC) GaRDe : Gametes and RNA Decay (Norbert GHYSELINCK partner)
  • ANR 2020 (PRC) ARDIGERM : Retinoic acid for germ cell differentiation and meiosis (Norbert GHYSELINCK coordinator)
  • Ministry of Solidarity and Health 2018 (PHRC-I) ARESPERM : Retinoic acid and sperm production in infertile men (Marius TELETIN coordinator)
  • ANR 2017 (JCJC) CORNUSPERM : Nuclear Receptor Coregulators in Spermatogenesis (Nadège VERNET coordinator)
  • ANR 2016 (PRC) ARESSERC : Deciphering non-canonical pathways controlled by retinoic acid in vivo using Sertoli cells as a model (Norbert GHYSELINCK coordinator)

Former members

Valérie DUPE (Researcher, Inserm), ORCID ID, Institute of Genetics and Development of Rennes (IGDR, UMR 6290 CNRS) , Rennes, France. Team Genetics of disorders related to neurectodermal development



Olivia WENDLING (IR, CNRS), Mouse Clinic Institute (ICS), Phenotyping Department, Illkirch, France. Team Histopathology and Embryology




Nicolas MATT (Professor, UNISTRA), Institute Molecular and Cellular Biology of Strasbourg (IBMC-M3i, UPR 9022 CNRS) , Strasbourg, France. Team Genetics of immune response, Vice-Président Patrimoine UNISTRA



Bénédicte MASCREZ (Associate scientist), University of Genève, Department of Genetics and Evolution, Geneva, Swiss. Team Developmental Genomics




Frank SCHNUTGEN (Lab manager), ORCID ID, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Frankfurt am Main, Hessen, Germany. Serve Lab




Hugues JACOB (IR CERBM-GIE), Mouse Clinic Institute (ICS), Phenotyping Department, Illkirch, France. Team Histopathology and Embryology




Mathilde RAVERDEAU (post-doctorate), ORCID ID, Trinity College Dublin, School of Biochemistry and Immunology, Immune Regulation Research, Dublin, Ireland. Team



Aurore GELY-PERNOT (Associate Professor, EHESP), ORCID ID:, Institut de recherche en santé, environnement et travail (IRSET, Inserm UMR 1085), Rennes, France. Equipe Physiologie et physiopathologie du tractus uro-génital and School of Public Health (EHESP), Department of environmental and occupational health, Rennes, France



Sirine SOUALI-CRESPO (post-docotorate)

Awards and recognitions

Nadège VERNET, CNRS bronze medal in 2021


Functional genomics and cancer - Rare diseases