Retinol dehydrogenase 10 is indispensible for spermatogenesis in juvenile males

Abstract

Retinoic acid (RA), an active vitamin A derivative, is essential for mammalian spermatogenesis. Genetic studies have revealed that oxidation of vitamin A to retinal by retinol dehydrogenase 10 (RDH10) is critical for embryonic RA biosynthesis. However, physiological roles of RDH10 in postnatal RA synthesis remain unclear, given that Rdh10 loss-of-function mutations lead to early embryonic lethality. We conducted in vivo genetic studies of Rdh10 in postnatal mouse testes and found that an RDH10 deficiency in Sertoli cells, but not in germ cells, results in a mild germ cell depletion phenotype. A deficiency of RDH10 in both Sertoli and germ cells in juvenile mice results in a blockage of spermatogonial differentiation, similar to that seen in vitamin A-deficient animals. This defect in spermatogenesis arises from a complete deficiency in juvenile testicular RA synthesis and can be rescued by retinoid administration. Thus, in juvenile mice, the primary, but not exclusive, source of RA in the testes is Sertoli cells. In contrast, adult Rdh10 -deficient mice exhibit phenotypically normal spermatogenesis, indicating that during development a change occurs in either the cellular source of RA or the retinaldehyde dehydrogenase involved in RA synthesis.

Germ Cell Commitment to Oogenic Versus Spermatogenic Pathway: The Role of Retinoic Acid

“…Data derived from developmental studies indicate that ALDH1A1 and ALDH1A3 are mostly active within tissues of ectodermal origin, i.e., the brain and eyes, whereas ALDH1A2 is more broadly present throughout the mesodermal tissues, including the gonad. Transcript and protein localization studies and global and conditional mouse mutants, which will be described in the following sections, have demonstrated a role for RDH10 and all three ALDH enzymes in the synthesis of RA within the testis Sugimoto et al 2012;Tong et al 2013;Vernet et al 2006b), yet there is significantly less known about which isozymes are expressed or essential for germ cell development in the fetal ovary. The current dogma suggests that RA acts in a paracrine manner: synthesized by one cell and then passed to a neighboring cell to induce a response .…”

Retinoid signaling controls spermatogonial differentiation by regulating expression of replication-dependent core histone genes

“…We and others have demonstrated that testicular RA mainly originates from Sertoli cells especially in puberty; however, it remains elusive whether the action of RA on spermatogonial differentiation is through germ cells or Sertoli cells, or both Sertoli and germ cells, as its receptors, RARs and RXRs, are expressed in both Sertoli cells and the undifferentiated spermatogonia (Gely-Pernot et al, 2012;Tong et al, 2013;Vernet et al, 2006b;Gaemers et al, 1998;DeFalco et al, 2015). For instance, genetic ablation of Rarg in germ cells resulted in only mild spermatogonial differentiation defects in mutants younger than one year old, indicating that either retinoid signaling in Sertoli cells is involved in spermatogonial differentiation, or that other subtypes of RARs in spermatogonia compensate for loss of RARγ function, as it is the case for many other developmental process (Gely-Pernot et al, 2012;Mark et al, 2009).…”

“…For EdU labeling, as described previously (Tong et al, 2013), mice were i.p. injected with EdU (Invitrogen) (50 μg/g body weight) in PBS.…”

Importance of ALDH1A enzymes in determining human testicular retinoic acid concentrations

“…An excellent model organ for the tissue-specifi c synthesis of at RA is the testis ( 28 ), as at RA synthesis within the testis is required for male fertility ( 29,30 ). For example, there is no initiation of spermatogenesis in mice which lack ALDH1A1, ALDH1A2, and ALDH1A3 in the Sertoli cells ( 30 ).…”