Retinoic Acid Receptors Control Spermatogonia Cell-Fate and Induce Expression of the SALL4A Transcription Factor

Aurore Gely-Pernot; Mathilde Raverdeau; Marius Teletin; Nadège Vernet; Betty Féret; Muriel Klopfenstein; Christine Dennefeld; Irwin Davidson; Gérard Benoit; Manuel Mark; Norbert B Ghyselinck

doi:10.1371/journal.pgen.1005501

Retinoic Acid Receptors Control Spermatogonia Cell-Fate and Induce Expression of the SALL4A Transcription Factor

PLoS Genet. 2015 Oct 1;11(10):e1005501. doi: 10.1371/journal.pgen.1005501. eCollection 2015 Oct.

Affiliations

¹ Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Génétique Fonctionnelle et Cancer, Illkirch, France; Centre National de la Recherche Scientifique (CNRS), UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U964, Illkirch, France; Université de Strasbourg (UNISTRA), Illkirch Cedex, France.
² Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Génétique Fonctionnelle et Cancer, Illkirch, France; Centre National de la Recherche Scientifique (CNRS), UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U964, Illkirch, France; Université de Strasbourg (UNISTRA), Illkirch Cedex, France; Hôpitaux Universitaires de Strasbourg (HUS), Strasbourg, France.
³ Centre de Génétique et de Physiologie Moléculaire et Cellulaire (GCPhiMC), UMR5534 CNRS, Université de Lyon 1, Villeurbanne, France.

Abstract

All-trans retinoic acid (ATRA) is instrumental to male germ cell differentiation, but its mechanism of action remains elusive. To address this question, we have analyzed the phenotypes of mice lacking, in spermatogonia, all rexinoid receptors (RXRA, RXRB and RXRG) or all ATRA receptors (RARA, RARB and RARG). We demonstrate that the combined ablation of RXRA and RXRB in spermatogonia recapitulates the set of defects observed both upon ablation of RAR in spermatogonia. We also show that ATRA activates RAR and RXR bound to a conserved regulatory region to increase expression of the SALL4A transcription factor in spermatogonia. Our results reveal that this major pluripotency gene is a target of ATRA signaling and that RAR/RXR heterodimers are the functional units driving its expression in spermatogonia. They add to the mechanisms through which ATRA promote expression of the KIT tyrosine kinase receptor to trigger a critical step in spermatogonia differentiation. Importantly, they indicate also that meiosis eventually occurs in the absence of a RAR/RXR pathway within germ cells and suggest that instructing this process is either ATRA-independent or requires an ATRA signal originating from Sertoli cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / genetics
DNA-Binding Proteins / biosynthesis*
DNA-Binding Proteins / genetics
Gene Expression Regulation, Developmental
Humans
Male
Meiosis / genetics
Mice
Proto-Oncogene Proteins c-kit / genetics*
Proto-Oncogene Proteins c-kit / metabolism
Retinoid X Receptors / genetics
Sertoli Cells / metabolism
Spermatogenesis / genetics
Spermatogonia / growth & development*
Spermatogonia / metabolism
Transcription Factors / biosynthesis*
Transcription Factors / genetics
Tretinoin / metabolism*

Substances

DNA-Binding Proteins
Retinoid X Receptors
Sall4 protein, mouse
Transcription Factors
Tretinoin
Proto-Oncogene Proteins c-kit

Grants and funding

This work was supported by grants from CNRS, INSERM, UNISTRA, Agence Nationale pour la Recherche (ANR 09-BLAN-0282; 10-BLAN-1239; 13-BSV2-0017), Fondation pour la Recherche Médicale (FDT20110922849; DEQ20071210544) and European community (FP7-PEOPLE-2012-IEF Marie Curie action, project #331687). It was also supported in part by the grant ANR-10-LABX-0030-INRT under the frame program Investissements d'Avenir labeled ANR-10-IDEX-0002-02. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.