title: Retinoic acid induces Sertoli cell paracrine signals for spermatogonia differentiation but cell autonomously drives spermatocyte meiosis.
abstract: Direct evidence for a role of endogenous retinoic acid (RA), the active metabolite of vitamin A in the initial differentiation and meiotic entry of spermatogonia, and thus in the initiation of spermatogenesis is still lacking. RA is synthesized by dedicated enzymes, the retinaldehyde dehydrogenases (RALDH), and binds to and activates nuclear RA receptors (RARA, RARB, and RARG) either within the RA-synthesizing cells or in the neighboring cells. In the present study, we have used a combination of somatic genetic ablations and pharmacological approaches in vivo to show that during the first, prepubertal, spermatogenic cycle (i) RALDH-dependent synthesis of RA by Sertoli cells (SC), the supporting cells of the germ cell (GC) lineage, is indispensable to initiate differentiation of A aligned into A1 spermatogonia; (ii) RARA in SC mediates the effects of RA, possibly through activating Mafb expression, a gene whose Drosophila homolog is mandatory to GC differentiation; (iii) RA synthesized by premeiotic spermatocytes cell autonomously induces meiotic initiation through controlling the RAR-dependent expression of Stra8. Furthermore, we show that RA of SC origin is no longer necessary for the subsequent spermatogenic cycles but essential to spermiation. Altogether, our data establish that the effects of RA in vivo on spermatogonia differentiation are indirect, via SC, but direct on meiotic initiation in spermatocytes, supporting thereby the notion that, contrary to the situation in the female, RA is necessary to induce meiosis in the male.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7104, Institut National de la Santé et de la Recherche Médicale Unité 964, Université de Strasbourg, Illkirch, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Raverdeau
authors.forename: Aurore
authors.initials: A
authors.lastname: Gely-Pernot
authors.forename: Betty
authors.initials: B
authors.lastname: Féret
authors.forename: Christine
authors.initials: C
authors.lastname: Dennefeld
authors.forename: Gérard
authors.initials: G
authors.lastname: Benoit
authors.forename: Irwin
authors.initials: I
authors.lastname: Davidson
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Manuel
authors.initials: M
authors.lastname: Mark
authors.forename: Norbert B
authors.initials: NB
authors.lastname: Ghyselinck
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008540:Meiosis / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019899:Paracrine Communication / Q000187:drug effects / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012708:Sertoli Cells / Q000187:drug effects* / Q000378:metabolism; D013090:Spermatocytes / Q000187:drug effects* / Q000378:metabolism; D013093:Spermatogonia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C515028:ALDH1A1 protein, mouse; C512722:Aldh1a2 protein, mouse; D050697:Retinal Dehydrogenase