Sources ofall-transretinal oxidation independent of the aldehyde dehydrogenase 1A isozymes exist in the postnatal testis†

Abstract

Despite the essential role of the active metabolite of vitamin A, all-trans retinoic acid (atRA) in spermatogenesis, the enzymes, and cellular populations responsible for its synthesis in the postnatal testis remain largely unknown. The aldehyde dehydrogenase 1A (ALDH1A) family of enzymes residing within Sertoli cells is responsible for the synthesis of atRA, driving the first round of spermatogenesis. Those studies also revealed that the atRA required to drive subsequent rounds of spermatogenesis is possibly derived from the ALDH1A enzymes residing within the meiotic and post-meiotic germ cells. Three ALDH1A isozymes (ALDH1A1, ALDH1A2, and ALDH1A3) are present in the testis. Although, ALDH1A1 is expressed in adult Sertoli cells and is suggested to contribute to the atRA required for the pre-meiotic transitions, ALDH1A2 is proposed to be the essential isomer involved in testicular atRA biosynthesis. In this report, we first examine the requirement for ALDH1A2 via the generation and analysis of a conditional Aldh1a2 germ cell knockout and a tamoxifen-induced Aldh1a2 knockout model. We then utilized the pan-ALDH1A inhibitor (WIN 18446) to test the collective contribution of the ALDH1A enzymes to atRA biosynthesis following the first round of spermatogenesis. Collectively, our data provide the first in vivo evidence demonstrating that animals severely deficient in ALDH1A2 postnatally proceed normally through spermatogenesis. Our studies with a pan-ALDH1A inhibitor (WIN 18446) also suggest that an alternative source of atRA biosynthesis independent of the ALDH1A enzymes becomes available to maintain atRA levels for several spermatogenic cycles following an initial atRA injection.

Retinoic acid signaling pathways

“…RA produced by spermatocytes and Sertoli cells acts redundantly to maintain spermatogenesis ALDH1A generates RA in spermatocytes, but is fully dispensable for spermatogenesis (Beedle et al, 2019;Teletin et al, 2019). Initially, this suggested that ALDH1A-independent sources of RA could compensate for the loss of Aldh1a2 in spermatocytes (Beedle et al, 2019).…”

“…RA produced by spermatocytes and Sertoli cells acts redundantly to maintain spermatogenesis ALDH1A generates RA in spermatocytes, but is fully dispensable for spermatogenesis (Beedle et al, 2019;Teletin et al, 2019). Initially, this suggested that ALDH1A-independent sources of RA could compensate for the loss of Aldh1a2 in spermatocytes (Beedle et al, 2019). However, analysis of compound mutant mice demonstrates that ALDH1A-dependent activities account for all of the RA required for spermatogenesis, and that the Sertoli and spermatocyte sources of RA exert redundant functions in spermatogenesis maintenance (Teletin et al, 2019).…”

Retinoic Acid and Germ Cell Development in the Ovary and Testis

“…In the unperturbed testis, RA from Sertoli cells contributes functionally to both spermatogonial differentiation and meiotic initiation [19]. Recent studies have addressed the question of whether RA produced by pachytene spermatocytes is required for spermatogenesis [19,171,172]. Chemical or genetic depletion of pachytene spermatocytes in adult testes results in delays to both the elongation of the round spermatids and spermiation, but not to spermatogonial differentiation or meiotic initiation [19].…”

“…Conversely, after injection of RA at 4 weeks of age, Sertoli cell-specific Aldh1a1-3-deficient adults displayed abnormalities in spermiation at 24 weeks of age [63], suggesting that RA from Sertoli cells contributes modestly to this process. Moreover, the level of RA required for spermatogonial differentiation is higher than that required for meiotic initiation [171,172], indicating that each transition is sensitive to the local level of RA. Because the postmeiotic transitions are most sensitive following depletion of RA [19], the postmeiotic transitions may require a higher concentration of RA, from both Sertoli cells and pachytene spermatocytes, than the premeiotic transitions.…”

Recent insights on the role and regulation of retinoic acid signaling during epicardial development

“…Even so, the great redundancy present in the retinoid metabolome, prevents us from establishing a complete list of the enzymes responsible for many important biotransformations of retinoids. Nonetheless, the knowledge of the main embryonic retinoid enzymes provides us with tools to study the roles of endogenous RA by manipulating its levels in tissue-specific manner through conditional gene targeting (Arregi et al, 2016;Beedle et al, 2019;Bonney, Dennison, Wendlandt, & Siegenthaler, 2018;Kumar, Dolle, Ghyselinck, & Duester, 2017).…”