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Pathophysiology of vitamin A signaling pathways

Pathophysiology of vitamin A signaling pathways

DEPARTMENT

Functional genomics and cancer

TEAM LEADER

Norbert GHYSELINCK

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.

Resources

 

Deconstructing and reconstructing embryos

https://youtu.be/Go8G-9agNW4

https://moodle.unistra.fr/course/view.php?id=13647

Choose: anonymous connexion

Password: ontogenesis

Members

Researchers

Technicians

Research subgroup(s)

Collaborations and networks

Gérard BENOIT, ORCID ID orcid.org/0000-0003-3148-4127 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 http://www.ens-lyon.fr/LBMC/equipes/systems-biology-of-decision-making/themes-de-recherche/deciphering-nuclear-receptor-biological-function-in-differentiating-mouse-pluripotent-embryonic-cells

 

 

Marie-Christine CHABOISSIER, ORCID ID orcid.org/0000-0003-0934-8217 Institute Biologie Valrose (iBV, INSERM U1091, CNRS UMR 7277), Nice-Côte d’Azur University, Nice, France. Team Sex determination in mice ibv.unice.fr/research-team/chaboissier/

 

 

Frédéric CHALMEL, ORCID ID orcid.org/0000-0002-0535-3628 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 www.irset.org/en/axis-4-gonad-differentiation-and-physiology

 

 

Gregg DUESTER, ORCID ID orcid.org/0000-0003-4335-3650 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 www.sbpdiscovery.org/our-scientists/gregg-duester-phd

 

 

Pierre GERMAIN, ORCID ID orcid.org/0000-0003-2962-9593 Centre de Biologie Structurale (CBS, CNRS UMR 5048, INSERM U 1054), Montpellier, France. Team Nuclear Receptors as Integrators of Endogenous and Environmental Signals www.cbs.cnrs.fr/index.php/en/home-equipea5

 

 

 

Gabriel LIVERA, ORCID ID orcid.org/0000-0001-8436-4730 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. jacob.cea.fr/drf/ifrancoisjacob/english/Pages/Departments/IRCM/Teams/LDG.aspx

 

 

 

Serge NEF, ORCID ID orcid.org/0000-0001-5462-0676 University of Genève, Department of Genetic Medicine and Development, Geneva, Swiss. Team Molecular and Developmental Biology of Sexual Development www.unige.ch/medecine/nef/

 

 

 

Eric PAILHOUX, ORCID ID orcid.org/0000-0001-8012-9143 Biology of Reproduction, Environnement, Epigenetics, and Development (BREED, INRAE UMR 1198), Jouy-en-Josas, France. Team Gonad Differentiation and its Perturbations www6.jouy.inrae.fr/breed_eng/Our-Research/Scientific-teams/Gonad-Differentiation-and-its-Perturbations-DGP

 

 

 

Bertrand SERAPHIN, ORCID ID orcid.org/0000-0002-5168-1921 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 www.igbmc.fr/research/department/2/team/27/  

 

 

Michael WEBER, ORCID ID orcid.org/0000-0003-3484-5821 Biotechnology and Cell Signalling (BSC, CNRS UMR 7242), ESBS, Illkirch, France. Team Epigenetic regulation of cell identity bsc.unistra.fr/en/research-teams/team-weber/presentation/

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)

Awards and recognitions

Nadège VERNET, CNRS bronze medal in 2021 www.cnrs.fr/en/node/5613

Publications

Functional genomics and cancer - Rare diseases