Global Deletion of ALDH1A1 and ALDH1A2 Genes Does Not Affect Viability but Blocks Spermatogenesis

Abstract

The transition of undifferentiated A spermatogonia to differentiated spermatogonia requires the action of retinoic acid (RA). The synthesis of retinoic acid from retinal in the seminiferous epithelium is a result of the action of aldehyde dehydrogenases termed ALDH1A1, ALDH1A2, and ALDH1A3. We used a mouse with a global deletion of the Aldh1a1 gene that is phenotypically normal and the CRE-loxP approach to eliminate Aldh1a2 genes globally and from Sertoli cells and germ cells. The results show that global elimination of Aldh1a1 and Aldh1a2 genes blocks spermatogenesis but does not appear to affect viability. The cell specific elimination of Aldh1a2 gene showed that retinoic acid synthesis by Sertoli cells is required for the initial round of spermatogonial differentiation but that there is no requirement for retinoic acid synthesis by germ cells. In both the global gene deletion and the cell specific gene deletions the maintenance of Aldh1a3 activity could not compensate.

The Role of Retinoic Acid in Spermatogenesis and Its Application in Male Reproduction

“…The specific knockdown of RALDH2 in germ cells resulted in mice with no abnormalities in spermatogenesis and no reduction in testicular RA levels [14]. However, the deletion of the ALDH1A1 and ALDH1A2 genes in the Sertoli cells can completely block the onset of spermatozoa conversion from A spermatogonia to A1, and this blockage can be cured through the injection of RA [15]. It is indicated that the production of RA by Sertoli cells through the ALDH1A1 or ALDH1A2 enzyme is necessary to initiate spermatogenesis.…”

Male Contraception

“…54 Mice lacking the genes for synthesis or action are sterile. 55,56 As a result, developing approaches to block retinoic acid function or production in the testes has been studied as an approach to male contraceptive development. For example, the oral administration of BMS-189453, an antagonist of all three retinoic acid receptors, led to reversible suppression of spermatogenesis and fertility in rats and mice.…”

Core binding factor subunit β plays diverse and essential roles in the male germline

“…First, the undifferentiated spermatogonia population is formed, which includes spermatogonial stem cells (SSC), that will maintain the germline indefinitely by producing daughter cells that eventually differentiate to form sperm. Second, during prepubertal development, the first spermatocytes are produced, which become the replenishing source of retinoic acid (RA) necessary to sustain spermatogenesis (Raverdeau et al, 2012;Tong et al, 2013;Teletin et al, 2018;Griswold, 2022;Topping and Griswold, 2022). Finally, more recent studies have demonstrated that lumicrine factors such as NELL2 and NICOL are produced during the onset of spermatogenesis to promote the maturation of the epididymis, which is necessary for fertility (Kiyozumi et al, 2020;Kiyozumi et al, 2023).…”