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

Abstract

Retinoic acid (RA) signaling is critical 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 RA receptor α (RARα) specifically to the germ cells of transgenic mice to subvert the activity of endogenous receptors. Here we show that (i) inhibition of retinoid signaling in germ cells completely blocked spermatogonial differentiation identical to vitamin A-deficient (VAD) mice; (ii) the blockage of spermatogonial differentiation by impaired retinoid signaling resulted from an arrest of entry of the undifferentiated spermatogonia into S phase; and (iii) retinoid signaling regulated spermatogonial differentiation through controlling expression of its direct target genes including replication-dependent core histone genes. Altogether, our results demonstrate that the action of retinoid signaling on spermatogonial differentiation in vivo is direct through spermatogonia self, and provide the first evidence that this is mediated by regulation of expression of replication-dependent core histone genes.