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

Abstract

Retinoic acid (RA) signaling is crucial for spermatogonial differentiation, which is a key step for spermatogenesis. We explored the mechanisms underlying spermatogonial differentiation by targeting expression of a dominant-negative mutant of retinoic acid receptor α (RARα) specifically to the germ cells of transgenic mice to subvert the activity of endogenous receptors. Here we show that: (1) inhibition of retinoid signaling in germ cells completely blocked spermatogonial differentiation identical to vitamin A-deficient (VAD) mice; (2) the blockage of spermatogonial differentiation by impaired retinoid signaling resulted from an arrest of entry of the undifferentiated spermatogonia into S phase; and (3) retinoid signaling regulated spermatogonial differentiation through controlling expression of its direct target genes, including replication-dependent core histone genes. Taken together, our results demonstrate that the action of retinoid signaling on spermatogonial differentiation in vivo is direct through the spermatogonia itself, and provide the first evidence that this is mediated by regulation of expression of replication-dependent core histone genes.

Roles of Retinoic Acid in Germ Cell Differentiation

“…In agreement with this proposal, the amount of SALL4 protein detected in spermatogonia is higher at the A1 stage than at the Aal stage (Hobbs et al, 2012). In addition to SALL4, a recent study shows that ATRA controls spermatogonia differentiation through activating replicationdependent core histone genes (Chen et al, 2016).…”

Retinoic acid and androgens interact to regulate spermatogenesis in a non-mammalian vertebrate lackingstra8

“…Still, spermatogonial differentiation, meiosis and the production of mature sperm occurs, resulting in a quite heterogeneous testis histology. This differs from the generalized block of spermatogonial differentiation found in mice using a similar transgenic approach (15). However, sperm quality was clearly compromised in these transgenic zebrafish, with reduced fertilization rates and a high mortality of the (few) resulting embryos within the first 24 hours of development.…”

“…Our results indicate that as in mammals (3, 7, 15) in zebrafish too, RA is required for spermatogonial differentiation. However, in zebrafish besides RA also androgens are crucial for spermatogonia to differentiate, as A und spermatogonia accumulate when androgen production is blocked.…”

“…Also, mice lacking different isoforms (α, β, γ) of the nuclear RA and retinoid X receptors (RARs and RXRs) showed testicular abnormalities or sterility (12) and germ cell apoptosis (13, 14). Dominant-negative mutant models of the RARα allowed further characterization of essential molecular functions of RA signaling for germ cell development (15, 16). It is not clear if the RA dependency of mammalian spermatogenesis represents an evolutionary conserved feature, as in this regard very little is known in non-mammalian vertebrates including fish, in this regard.…”

Regulation of GDNF expression in Sertoli cells

“…Under the influence of retinoic acid, A aligned cells differentiate into A 1 -A 4 cells, or differentiating spermatogonia, which further divide to become Intermediate spermatogonia, B spermatogonia, and primary spermatocytes. Spermatocytes will undergo meiosis and give rise to haploid spermatids that will progress through spermiogenesis to become spermatozoa (Haneji et al 1983, Russell et al 1990, van Pelt & de Rooij 1991, Chen et al 2016b, Griswold 2016. In human and non-human primates, the SSC population consists in A dark and A pale spermatogonia, distinguished by their size, nuclear morphology, and different intensity of hematoxylin staining (Clermont & Leblond 1959).…”