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.

Importance of ALDH1A enzymes in determining human testicular retinoic acid concentrations

“…The distinct ALDH1A localization in human testicular tissue suggests that each ALDH1A may play a different role in RA formation in different cell types of the testis. Previous work in knockout mice has shown that ALDH1A enzymes in Sertoli cells are responsible for the initial source of RA during spermatogenesis, while ALDH1A in spermatocytes may help maintain RA formation after the fi rst wave of spermatogenesis ( 30 ). This study shows that overall in the human testis, ALDH1A1 and ALDH1A2 contribute signifi cantly to formation of at RA from at -retinal and their relative contributions will depend on the interactions of the ALDH1A enzymes with CRBP1 in the specifi c cell types.…”

“…For example, there is no initiation of spermatogenesis in mice which lack ALDH1A1, ALDH1A2, and ALDH1A3 in the Sertoli cells ( 30 ). Similarly, an inhibitor of the ALDH1A enzymes, WIN 18,446, has been shown to affect the ability of multiple mammalian species, including humans, to produce sperm (31)(32)(33), likely due to decreased at RA concentrations in the testes ( 33 ).…”

“…An excellent model organ for the tissue-specifi c synthesis of at RA is the testis ( 28 ), as at RA synthesis within the testis is required for male fertility ( 29,30 ). For example, there is no initiation of spermatogenesis in mice which lack ALDH1A1, ALDH1A2, and ALDH1A3 in the Sertoli cells ( 30 ).…”

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

“…The promoters of Ezh2, Tgif1 and Zfp536 genes that negatively regulate the retinoic acid (RA) signaling pathway, show decreased H3K4me3 occupancy; in contrast, the region of Rxra have increased H3K4me3 occupancy. RA plays key roles in SG differentiation and is essential for meiosis initiation (94). Our data suggests that changed H3K4me3 marks within genes regulating RA pathway may play a role in impaired spermatogenesis.…”

SMAD2 and p38 signaling pathways act in concert to determine XY primordial germ cell fate in mice

“…It is also plausible that RA from the mesonephros remains because of incomplete degradation by CYP26B1 in somatic cells, because we could not exclude the possibility that p38 inhibitor affects the enzyme activity of CYP26B1. Moreover, recent studies also provided a controversial model that RA is required for meiotic initiation in male germ cells but not female germ cells by genetic deletion of retinaldehyde dehydrogenase 2 and 3 (Raldh2/3; Aldh1a2/3 -MGI) (Kumar et al, 2011;Raverdeau et al, 2012). …”