Abstract
Germ cells (Gc) propagate the genetic information to subsequent generations. Diploid (2n) Gc get transformed to specialized haploid (n) gametes by mitotic and meiotic divisions in adult gonads. Retinoic acid (RA), an active derivative of vitamin A (retinol), plays a critical role in organ morphogenesis and regulates the meiotic onset in developing Gc. Unlike ovaries, fetal testes express an RA-degrading enzyme CYP26B1, and thereby, male Gc fail to enter into meiosis and instead get arrested at G0/G1 stage, termed as gonocytes/pro-spermatogonia by embryonic (E) 13.5 days. These gonocytes are transformed into spermatogonial stem/progenitor cells after birth (1–3 days of neonatal age). During post-natal testicular maturation, the differentiating spermatogonia enter into the meiotic prophase under the influence RA, independent of gonadotropic (both FSH and LH) support. The first pulse of RA ensures the transition of undifferentiated type A spermatogonia to differentiated A1 spermatogonia and upregulates STRA8 expression in Gc. Whereas, the second pulse of RA induces the meiotic prophase by augmenting MEIOSIN expression in differentiated spermatogonia B. This opinion article briefly reviews our current understanding on the RA-driven spermatogonial differentiation in murine testes.
Highlights
Spermatogenesis occurs within testes where male germ cells (Gc) undergo both mitotic and meiotic divisions to form haploid (n) spermatozoa (Griswold, 2016)
After the arrival at the genital ridge (GR)/bipotential gonad, primordial germ cells (PGC) undergo a massive global demethylation during E 10.5–12.5 days (Seisenberger et al, 2012). This extensive epigenetic reprogramming leads to the induction of RNA-binding proteins Dazl and Ddx4 (DEAD box polypeptide 4, called mouse vasa homolog), and PGC get transformed into gametogenesis-competent cells (GCC) (Lin et al, 2008)
Retinoic acid (RA) acts on the differentiating spermatogonia A via both classical genomic or non-genomic pathways to induce 1) genes required for G1/S phase transition (e.g., Hist1 and Ccnd2), 2) genes critical for initiating spermatogonial differentiation (c-Kit and Sall4), and 3) genes to promote the meiotic prophase [Stra8; Rec8; and subsequently Dmc1, Sycp3, etc.] (Chen et al, 2016)
Summary
Spermatogenesis occurs within testes where male germ cells (Gc) undergo both mitotic and meiotic divisions to form haploid (n) spermatozoa (Griswold, 2016). This is a tightly regulated asynchronized process, broadly sub-divided into four major developmental stages, namely, 1) pre-meiotic proliferation of undifferentiated spermatogonia, 2) meiotic entry of differentiated spermatogonia 3) meiotic completion and formation of round spermatid, and 4) maturation of elongated spermatid to spermatozoa (Griswold, 2016). Testicular Sertoli cells (Sc) provide the structural and biochemical support to all the stages of male Gc within the seminiferous tubules (Griswold, 2018; Bhattacharya et al, 2019) Both Gc-specific intrinsic and Sc-derived extrinsic factors collectively determine the Gc developmental fate (Griswold, 2018; Bhattacharya et al, 2019). During post-natal testicular maturation, RA induces the transition of undifferentiated spermatogonia A to
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