Initiating Meiosis: The Case for Retinoic Acid1

Abstract

The requirement for vitamin A in reproduction and development was first determined from studies of nutritional deficiencies. Subsequent research has shown that embryonic development and both male and female reproduction are modulated by retinoic acid (RA), the active form of vitamin A. Because RA is active in multiple developmental systems, its synthesis, transport, and degradation are tightly regulated in different tissues. A growing body of evidence implicates RA as a requirement for the initiation of meiosis in both male and female mammals, resulting in a mechanistic model involving the interplay of RA, RA synthesis enzymes, RA receptors, and degradative cytochrome P450 enzymes in this system. Recently, that model has been challenged, prompting a review of the established paradigm. While it remains possible that additional molecules may be involved in regulating entry into meiosis, the weight of evidence supporting a key role for RA is incontrovertible.

Dynamic expression pattern and subcellular localization of the Rhox10 homeobox transcription factor during early germ cell development

“…To determine whether Rhox10 is regulated by differentiation cues in spermatogonial cells, we treated GS cells with retinoic acid (RA), a known inducer of germ cell meiosis (Bowles et al 2006, Anderson et al 2008, Griswold et al 2012. We found that RA treatment for 24 h dramatically increased Rhox10 mRNA level (Fig.…”

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

“…This paradigm emerged from the ability of exogenous RA to induce premature meiotic initiation in fetal male GC (reviewed in ref. 5) and from VAD models, which display a meiotic failure simply because spermatogonia are blocked at the undifferentiated stage (e.g., ref. 35).…”

“…In fact, vitamin A-deficient (VAD) mice are infertile because of an arrest of spermatogonia differentiation at the Aal-A1 transition, and treating them with either retinol or RA results in the complete recovery of spermatogenesis (3). As RA can trigger meiosis in female GC through initiating Stra8 expression (4,5) and can additionally induce Stra8 expression in male GC (3), the paradigm has become that RA is required for meiotic initiation. However, a recent study showing that female GC can enter meiosis in a fetal ovary devoid of RA has challenged this model (6).…”

Inhibition of Retinoic Acid Biosynthesis by the Bisdichloroacetyldiamine WIN 18,446 Markedly Suppresses Spermatogenesis and Alters Retinoid Metabolism in Mice

“…The importance of vitamin A in reproductive health in both males and females has been well documented (1,2). In males, either vitamin A deficiency (3) or mutations in genes involved in retinoid signaling pathways leads to perturbations in meiosis and spermatogenesis (1,2).…”

“…In males, either vitamin A deficiency (3) or mutations in genes involved in retinoid signaling pathways leads to perturbations in meiosis and spermatogenesis (1,2). Because animals lack enzymes to synthesize vitamin A de novo, it has to be derived from dietary sources as preformed vitamin A from animal products and provitamin A carotenoids from fruits and vegetables (4).…”