Initiating meiosis: the case for retinoic acid

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.

FIG. 1.

The current paradigm for RA driving the onset of meiosis in males and females. A) In the embryonic ovary, RA (green triangles) generated in the mesonephros drives the expression of Stra8 and the onset of meiosis in the oogonia (pink). In the male embryo, RA is still produced in the mesonephros; however, the action of CYP26B1 (red stars), an RA-metabolizing enzyme that is made by Sertoli cells and testicular interstitial cells, acts to degrade this RA, thereby preventing Stra8 expression and the onset of meiosis. B) In the postnatal testis, there are several possible ways in which RA might be generated and delivered to spermatogonia. Retinol (ROL) may be internalized by either Sertoli cells or spermatogonia and converted first to retinaldehyde (RETALDH) and then to RA via a two-step process catalyzed by the alcohol dehydrogenases (ADH) and the aldehyde/retinaldehyde dehydrogenases (RALDH). Retinoic acid may also be delivered directly from the serum. Once inside the cell, RA can interact with RARs and stimulate transcription of a number of genes, including Stra8. The expression of Stra8 in spermatogonia, stimulated by RA, is coincident with the transition from undifferentiated type A spermatogonia to differentiated type A1 spermatogonia. Excess RA can be metabolized by the enzyme CYP26B1 into 4-oxo (OXO) and 4-hydroxy (OH) forms. These retinoid forms are then secreted from the cell.