Retinoic acid and androgens interact to regulate spermatogenesis in a non-mammalian vertebrate lackingstra8 (original) (raw)
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Development, 2019
Retinoic acid (RA) is critical for mammalian spermatogonia differentiation, and stimulates Stra8 expression, a gene required for meiosis. Certain fish species, including zebrafish, have lost the stra8 gene. While RA still seems important for spermatogenesis in fish, it is not known which stage(s) respond to RA or if its effects are integrated into the endocrine regulation of spermatogenesis. In zebrafish, RA promoted spermatogonia differentiation, supported androgen-stimulated meiosis and reduced spermatocyte and spermatid apoptosis. Follicle-stimulating hormone (Fsh) stimulated RA production. Expressing a dominant-negative RA receptor variant in germ cells clearly disturbed spermatogenesis but meiosis and spermiogenesis still took place although sperm quality was low in 6 months-old adults. This condition also activated Leydig cells. Three months later, spermatogenesis apparently had recovered, but doubling of testis weight demonstrated hypertrophy, apoptosis/DNA damage among sperm...
Spermatogonia Differentiation Requires Retinoic Acid Receptor γ
Endocrinology, 2012
Vitamin A is instrumental to mammalian reproduction. Its metabolite, retinoic acid (RA), acts in a hormone-like manner through binding to and activating three nuclear receptor isotypes, RA receptor (RAR)α (RARA), RARβ, and RARγ (RARG). Here, we show that 1) RARG is expressed by A aligned (Aal) spermatogonia, as well as during the transition from Aal to A1 spermatogonia, which is known to require RA; and 2) ablation of Rarg, either in the whole mouse or specifically in spermatogonia, does not affect meiosis and spermiogenesis but impairs the Aal to A1 transition in the course of some of the seminiferous epithelium cycles. Upon ageing, this phenomenon yields seminiferous tubules containing only spermatogonia and Sertoli cells. Altogether, our findings indicate that RARG cell-autonomously transduces, in undifferentiated spermatogonia of adult testes, a RA signal critical for spermatogenesis. During the prepubertal spermatogenic wave, the loss of RARG function can however be compensated...
Biology of Reproduction, 2010
Throughout the reproductive lifespan of most male mammals, sperm production is constant because of the regulated differentiation of spermatogonia. Retinoic acid (RA) and a downstream target, Stra8, are required for complete spermatogenesis. To examine the role of RA in initiating spermatogonial differentiation, a transgenic mouse model expressing beta-galactosidase under the control of an RA response element was used. Cells in the neonatal testis undergoing active RA signaling were visualized by beta-galactosidase activity, the relationship between RA and differentiation determined, and the role of RAdegrading enzymes in regulating RA demonstrated. Betagalactosidase activity was found to be predominantly associated with differentiating, premeiotic germ cells and to be distributed nonuniformly throughout the seminiferous tubules. Additionally, beta-galactosidase activity in premeiotic germ cells colocalized with STRA8 protein and was induced in germ cells with exogenous RA treatment. The RA-degrading enzyme, CYP26B1, was found to have germ cell localization and nonuniform distribution between tubules via immunohistochemistry. Treatment with a CYP26 enzyme inhibitor resulted in an increased number of germ cells with both beta-galactosidase activity and STRA8 protein and an increase in the expression of genes associated with differentiation and reduced expression of a gene associated with undifferentiated germ cells. These results show the action of RA in a subset of spermatogonia leads to nonuniform initiation of differentiation throughout the neonatal testis, potentially mediated through the action of CYP26 enzymes. Thus, the presence of RA is a likely driving factor in the initiation of spermatogonial differentiation and may result in asynchronous spermatogenesis.
Journal of Endocrinology, 2009
Androgens can induce complete spermatogenesis in immature or prepubertal teleost fish. However, many aspects of the role of androgens in adult teleost spermatogenesis have remained elusive. Since oestrogens inhibit androgen synthesis, we used an oestrogen-induced androgen depletion model to identify androgen-dependent stages during adult zebrafish spermatogenesis. Exposure to 10 nM 17b-oestradiol (E 2 ) in vivo at least halved the mass of differentiating germ cells (from type B spermatogonia to spermatids), while type A spermatogonia accumulated. Studies on the cellular dynamics revealed that a reduction of spermatogonial proliferation together with an inhibition of their differentiation to type B spermatogonia were the basis for the oestrogen-mediated disturbance of spermatogenesis. The capacity of the zebrafish testis to produce 11-ketotestosterone as well as the expression of steroidogenesis-related genes was markedly decreased after in vivo oestrogen exposure. Moreover, the androgen-release response to recombinant zebrafish Lh was lost after oestrogen exposure. We conclude that oestrogen exposure caused a state of androgen insufficiency in adult male zebrafish. Since the downregulation of the steroidogenic system as well as the disturbance of spermatogenesis in testicular explants exposed to E 2 ex vivo was much less severe than after in vivo exposure, the main inhibitory effect appears to be exerted via feedback inhibition of gonadotropin release. This experimental set-up helped to identify spermatogonial proliferation and their differentiation as androgen targets in adult zebrafish spermatogenesis.
Estrogen-induced inhibition of spermatogenesis in zebrafish is largely reversed by androgen
Journal of molecular endocrinology, 2018
The hormonal regulation of spermatogenesis involves both gonadotropins and steroid hormones. Long-term exposure of adult zebrafish to estrogen impaired spermatogenesis associated with an androgen insufficiency, possibly induced by inhibiting gonadotropin release. Using this experimental model, we investigated if androgen treatment could enhance spermatogenesis, while maintaining the inhibition of gonadotropin release through continued estrogen exposure. Moreover, we also exposed animals to androgen alone, in order to examine androgen effects in the absence of estrogen-induced gonadotropin inhibition. Estrogen exposure depleted type B spermatogonia, meiotic and postmeiotic germ cells from the adult testis, but promoted the proliferation of type A undifferentiated spermatogonia, which accumulated in the testis. This change in germ cell composition was accompanied by reduced mRNA levels of those growth factors (e.g. and ) expressed by testicular somatic cells and known to stimulate spe...
Development
In the mammalian testis, sustained spermatogenesis relies on spermatogonial stem cells (SSCs); their progeny either remain as stem cells (self-renewal) or proliferate and differentiate to enter meiosis in response to retinoic acid (RA). Here, we sought to uncover elusive mechanisms regulating a key switch fundamental to spermatogonial fate: the capacity of spermatogonia to respond to RA. Using the developing mouse testis as a model, we found that spermatogonia and precursor prospermatogonia exhibit a heterogeneous capacity to respond to RA with at least two underlying causes. First, progenitor spermatogonia are prevented from responding to RA by catabolic activity of cytochrome P450 family 26 enzymes. Second, a smaller subset of undifferentiated spermatogonia enriched for SSCs exhibit catabolism-independent RA insensitivity. Moreover, for the first time, we observed that precursor prospermatogonia are heterogeneous and comprise subpopulations that exhibit the same differential RA responsiveness found in neonatal spermatogonia. We propose a novel model by which mammalian prospermatogonial and spermatogonial fates are regulated by their intrinsic capacity to respond (or not) to the differentiation signal provided by RA before, and concurrent with, the initiation of spermatogenesis.
Recent Update on Retinoic Acid-Driven Initiation of Spermatogonial Differentiation
Frontiers in Cell and Developmental Biology, 2022
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 spermatogoni...
Insulin-like 3 affects zebrafish spermatogenic cells directly and via Sertoli cells
Communications Biology
Pituitary hormones can use local signaling molecules to regulate target tissue functions. In adult zebrafish testes, follicle-stimulating hormone (Fsh) strongly increases the production of insulin-like 3 (Insl3), a Leydig cell-derived growth factor found in all vertebrates. Little information is available regarding Insl3 function in adult spermatogenesis. The Insl3 receptors Rxfp2a and 2b were expressed by type A spermatogonia and Sertoli and myoid cells, respectively, in zebrafish testis tissue. Loss of insl3 increased germ cell apoptosis in males starting at 9 months of age, but spermatogenesis appeared normal in fully fertile, younger adults. Insl3 changed the expression of 409 testicular genes. Among others, retinoic acid (RA) signaling was up- and peroxisome proliferator-activated receptor gamma (Pparg) signaling was down-regulated. Follow-up studies showed that RA and Pparg signaling mediated Insl3 effects, resulting in the increased production of differentiating spermatogonia...
Prepubertal testis development relies on retinoic acid but not rexinoid receptors in Sertoli cells
The EMBO Journal, 2006
Sertoli cells (SC) are instrumental to stem spermatogonia differentiation, a process that critically depends on retinoic acid (RA). We show here that selective ablation of RA receptor alpha (RARalpha) gene in mouse SC, singly (Rara SerÀ/À mutation) or in combination with RARbeta and RARgamma genes (Rara/b/g SerÀ/À mutation), abolishes cyclical gene expression in these cells. It additionally induces testis degeneration and delays spermatogonial expression of Stra8, two hallmarks of RA deficiency. As identical defects are generated upon inactivation of RARalpha in the whole organism, our data demonstrate that all the functions exerted by RARalpha in male reproduction are Sertoli cell-autonomous. They further indicate that RARalpha is a master regulator of the cyclical activity of SC and controls paracrine pathways required for spermatogonia differentiation and germ cell survival. Most importantly, we show that the ablation of all RXR (alpha, beta and gamma isotypes) in SC does not recapitulate the phenotype generated upon ablation of all three RARs, thereby providing the first evidence that RARs exert functions in vivo independently of RXRs.
Rln3a is a prerequisite for spermatogenesis and fertility in male fish
The Journal of Steroid Biochemistry and Molecular Biology, 2019
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