Spermatogonia Differentiation Requires Retinoic Acid Receptor γ

Abstract

Vitamin A is instrumental to mammalian reproduction. Its metabolite, retinoic acid (RA), acts in a hormone-like manner through binding to and activating three nuclear receptor isotypes, RA receptor (RAR)α (RARA), RARβ, and RARγ (RARG). Here, we show that 1) RARG is expressed by A aligned (A(al)) spermatogonia, as well as during the transition from A(al) to A(1) spermatogonia, which is known to require RA; and 2) ablation of Rarg, either in the whole mouse or specifically in spermatogonia, does not affect meiosis and spermiogenesis but impairs the A(al) to A(1) transition in the course of some of the seminiferous epithelium cycles. Upon ageing, this phenomenon yields seminiferous tubules containing only spermatogonia and Sertoli cells. Altogether, our findings indicate that RARG cell-autonomously transduces, in undifferentiated spermatogonia of adult testes, a RA signal critical for spermatogenesis. During the prepubertal spermatogenic wave, the loss of RARG function can however be compensated by RARA, as indicated by the normal timing of appearance of meiotic cells in Rarg-null testes. Accordingly, RARG- and RARA-selective agonists are both able to stimulate Stra8 expression in wild-type prepubertal testes. Interestingly, inactivation of Rarg does not impair expression of the spermatogonia differentiation markers Kit and Stra8, contrary to vitamin A deficiency. This latter observation supports the notion that the RA-signaling pathway previously shown to operate in Sertoli cells also participates in spermatogonia differentiation.

Retinoic acid induces Sertoli cell paracrine signals for spermatogonia differentiation but cell autonomously drives spermatocyte meiosis

“…1 K-N; Fig. S1), which are markers of Aal spermatogonia (10,21). In contrast, KIT, which is expressed in A1 to B spermatogonia, was never detected in the seminiferous tubules of Aldh1a1-3 Ser−/− mutants ( Fig.…”

Retinoid signaling controls spermatogonial differentiation by regulating expression of replication-dependent core histone genes

“…We and others have demonstrated that testicular RA mainly originates from Sertoli cells especially in puberty; however, it remains elusive whether the action of RA on spermatogonial differentiation is through germ cells or Sertoli cells, or both Sertoli and germ cells, as its receptors, RARs and RXRs, are expressed in both Sertoli cells and the undifferentiated spermatogonia (Gely-Pernot et al, 2012;Tong et al, 2013;Vernet et al, 2006b;Gaemers et al, 1998;DeFalco et al, 2015). For instance, genetic ablation of Rarg in germ cells resulted in only mild spermatogonial differentiation defects in mutants younger than one year old, indicating that either retinoid signaling in Sertoli cells is involved in spermatogonial differentiation, or that other subtypes of RARs in spermatogonia compensate for loss of RARγ function, as it is the case for many other developmental process (Gely-Pernot et al, 2012;Mark et al, 2009). Thus, to better understand whether the modulation of spermatogonial differentiation by retinoid signaling occurs directly via the germ cells, it is necessary to completely inactivate retinoid signaling, specifically in germ cells.…”

“…Global inactivation of individual RAR genes such as Rara results in male sterility and aberrant spermatogenesis (Lufkin et al, 1993). Several lines of compound mutants lacking multiple RARs or RXRs have been studied in testis, suggesting that retinoid signaling plays a crucial role in spermatogonial differentiation (Gely-Pernot et al, 2012. However, the RA target genes implicated in spermatogonial differentiation need to be identified.…”

Periodic retinoic acid–STRA8 signaling intersects with periodic germ-cell competencies to regulate spermatogenesis

“…When VAD animals are injected with RA or vitamin A, the arrested spermatogonia differentiate (17)(18)(19), and the arrested preleptotene spermatocytes initiate meiosis (18). During spermatogonial differentiation, RA is believed to act, at least in part, directly on germ cells: Spermatogonia express RA receptors (RARs) (20), and genetic ablation of RARs in germ cells modestly impairs spermatogonial differentiation (21).…”