Potential roles of gonadotropins to control pulsatile retinoic acid signaling during spermatogenesis

Spermatogenesis is a highly regulated process that takes place in the seminiferous tubules of testis. This process initiates at puberty with differentiation of spermatogonia and their meiotic entry. The initiation of spermatogenesis depends on gonadotropins secreted by the pituitary gland; i.e., follicle-stimulating hormone (FSH) and luteinizing hormone (LH). In the absence of FSH and LH only premeiotic germ cells are present in the testis. The prepubertal development phase in juvenile testis is characterized by a protracted hypogonadotropic state, which only consists of Sertoli and undifferentiated germ cells in the seminiferous epithelium. All germ cells in the juvenile testis are undifferentiated spermatogonia, which are proliferating in a relatively gonadotropin-independent manner. It has been revealed that vitamin A deficient (VAD) animals are also infertile, and only premeiotic germ cells (undifferentiated spermatogonia) are present in their seminiferous tubules. The developmental block in VAD animal can be removed by administration of retinol and germ cell differentiation reinitiates in a synchronous manner. Recent studies have revealed that the biologically active form of vitamin A, retinoic acid (RA), regulates germ cell differentiation and lead to the generation of the cycle of the seminiferous epithelium and normal spermatogenic wave. Recent study has shown that synchronous spermatogenesis at neonatal mouse, but not after initiation of meiosis, can be induced by treating vitamin A sufficient males with RA. The treatment of neonatal males at different ages with exogenous RA has revealed that although RA is sufficient to induce differentiation of spermatogonial at 4 dpp and earlier, it fails to alter asynchrony and it does not irreversibly cause a spermatogonial differentiation. These observations led us to suggest that gonadotropins trigger differentiation of spermatogonia and spermatogenesis through regulation of RA signaling in the seminiferous epithelium of the adult testis.