Retinoic acid and differentiation of gametes – ARDIGAM

In the mammalian testis, sustained spermatogenesis relies on spermatogonia (SG) stem cells. Their progeny either remain as stem SG (for self-renewal) or they proliferate as distinct populations of SG progenitors, and differentiate. Later, differentiated SG enter meiosis to achieve genetic recombination and to halve the number of chromosomes, producing thereby haploid gametes (spermatozoa). Fertility ultimately depends not only on SG maintenance and differentiation, but also on proper spermatozoa release. Genetic and pharmacological studies in mice have revealed that retinoic acid (ATRA, the active metabolite of vitamin A) and its nuclear receptors (RARA, RARB and RARG) are major players in male gametogenesis. Our ARDIGAM project aims to demonstrate that distinct SG populations are essential to perpetuate spermatogenesis and to elucidate how RARA in the somatic, supporting, Sertoli cells (SC) and RARG in SG control the fate of each population (aim #1); and that ATRA works in SC by alternately activating and repressing genes required for spermatozoa production and release (aim #2). To do this, we have a collection, unique worldwide by its diversity, of mutant mice in which one or several actors of the ATRA signaling pathway are knocked out. We will apply an innovative approach allowing to capture simultaneously both the transcriptomic and the epigenetic signatures in given single SG and SC, across thousands of cells. Beyond gametogenesis and the treatment of male infertility, our project will help to understand how ATRA can control the differentiation of stem cell populations.