Antagonistic regulation of spermatogonial differentiation in zebrafish (Danio rerio) by Igf3 and Amh

Morais, Roberto D.V.S.; Crespo, Diego; Nóbrega, Rafael Henrique; Lemos, Moline Severino; Kant, H. J. G. van de; França, L. R.; Male, Rune; Bogerd, Jan; Schulz, Rüdiger

doi:10.1016/j.mce.2017.06.017

Cited by 49 publications

(49 citation statements)

References 88 publications

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“…Asterisks indicate significant differences (*P < 0.05) between basal and experimental group. D Safian et al 239:3 Journal of Endocrinology that zebrafish testis tissue also expresses several noncanonical Wnt receptors (Crespo et al 2016, Morais et al 2017. However, no information is available on the question which receptor specifically responds to WNT5a in mice or zebrafish testis tissue.…”

Section: Discussionmentioning

confidence: 99%

Fsh stimulates Leydig cell Wnt5a production, enriching zebrafish type A spermatogonia

Safian

Ryane

Bogerd

et al. 2018

Journal of Endocrinology

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Follicle-stimulating hormone (Fsh) modulates vertebrate spermatogenesis by regulating somatic cell functions in the testis. We have found previously that zebrafish Fsh stimulated the differentiating proliferation of type A undifferentiated spermatogonia (Aund) in an androgen-independent manner by regulating the production of growth factors and other signaling molecules in both Sertoli (SCs) and Leydig cells (LCs). For example, Fsh triggered the release of Igf3 that subsequently activated β-catenin signaling to promote the differentiating proliferation of Aund. In the present study, we report that Fsh moreover uses the non-canonical Wnt pathway to promote the proliferation and accumulation of Aund. Initially, we found that the stimulatory effect of Fsh on the proliferation activity of Aund was further strengthened when β-catenin signaling was inhibited, resulting in an accumulation of Aund. We then showed that this Fsh-induced accumulation of Aund was associated with increased transcript levels of the non-canonical Wnt ligand, wnt5a. In situ hybridization of insl3 mRNA, a gene expressed in LCs, combined with Wnt5a immunocytochemistry identified LCs as the cellular source of Wnt5a in the adult zebrafish testis. Addition of an antagonist of Wnt5a to incubations with Fsh decreased both the proliferation activity and the relative section area occupied by Aund, while an agonist of Wnt5a increased these same parameters for Aund. Taken together, our data suggest that Fsh triggered LCs to release Wnt5a, which then promoted the proliferation and accumulation of Aund. Hence, Fsh uses non-canonical Wnt signaling to ensure the production of Aund, while also triggering β-catenin signaling via Igf3 to ensure spermatogonial differentiation.

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Section: Discussionmentioning

confidence: 99%

Fsh stimulates Leydig cell Wnt5a production, enriching zebrafish type A spermatogonia

Safian

Ryane

Bogerd

et al. 2018

Journal of Endocrinology

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“…However, zebrafish Fsh also stimulates spermatogonial differentiation in an androgen-independent manner, for example by stimulating the release of Igf3 mainly from SCs (Nóbrega et al 2015) and of Insl3 from LCs (Assis et al 2016. Moreover, Fsh suppresses the production of the SC-derived anti-Müllerian hormone (Amh) (Skaar et al 2011), which would otherwise exert inhibitory effects on spermatogenesis (Morais et al 2017). Crespo et al (2016) identified ~200 testicular transcripts responding to zebrafish Fsh in an androgen-independent manner, including genes belonging to the Wnt signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Igf3 activates β-catenin signaling to stimulate spermatogonial differentiation in zebrafish

Safian

Bogerd

Schulz

2018

Journal of Endocrinology

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Follicle-stimulating hormone (Fsh) is a major regulator of spermatogenesis, targeting somatic cell functions in the testes. We reported previously that zebrafish Fsh promoted the differentiation of type A undifferentiated spermatogonia (A) by stimulating the production of factors that advance germ cell differentiation, such as androgens, insulin-like peptide 3 (Insl3) and insulin-like growth factor 3 (Igf3). In addition, Fsh also modulated the transcript levels of several other genes, including some belonging to the Wnt signaling pathway. Here, we evaluated if and how Fsh utilizes part of the canonical Wnt pathway to regulate the development of spermatogonia. We quantified the proliferation activity and relative section areas occupied by A and type A differentiating (A) spermatogonia and we analyzed the expression of selected genes in response to recombinant proteins and pharmacological inhibitors. We found that from the three downstream mediators of Fsh activity we examined, Igf3, but not 11-ketotestosterone or Insl3, modulated the transcript levels of two β-catenin sensitive genes ( and ). Using a zebrafish β-catenin signaling reporter line, we showed that Igf3 activated β-catenin signaling in type A spermatogonia and that this activation did not depend on the release of Wnt ligands. Pharmacological inhibition of the β-catenin or of the phosphoinositide 3-kinase (PI3K) pathways revealed that Igf3 activated β-catenin signaling in a manner involving PI3K to promote the differentiation of A to A spermatogonia. This mechanism represents an intriguing example for a pituitary hormone like Fsh using Igf signaling to recruit the evolutionary conserved, local β-catenin signaling pathway to regulate spermatogenesis.

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“…On the other hand, cortisol significantly increased the transcript level of amh (anti-Müllerian hormone) after 7 days of culture. Amh, a member of transforming growth factor β, is expressed in Sertoli cells [77,80], and exerts an important role in spermatogonial proliferation and differentiation, as reported in zebrafish and other fish species [80]. Moreover, studies have shown that Amh inhibits spermatogonial proliferation and differentiation in zebrafish testis [66,77,81].…”

Section: Discussionmentioning

confidence: 88%

“…We also examined whether cortisol-induced spermatogonial proliferation and differentiation could be mediated through a stimulatory growth factor, Igf3 (Insulin-like growth factor 3). Igf3 is a Sertoli cell derived growth factor that promotes spermatogonial proliferation and differentiation in the zebrafish testes [44,[77][78][79]. Cortisol treatment did not affect igf3 transcript level in the zebrafish testis.…”

Section: Discussionmentioning

confidence: 95%

Cortisol Directly Stimulates Spermatogonial Differentiation, Meiosis, and Spermiogenesis in Zebrafish (Danio rerio) Testicular Explants

et al. 2020

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Cortisol is the major endocrine factor mediating the inhibitory effects of stress on vertebrate reproduction. It is well known that cortisol affects reproduction by interacting with the hypothalamic–pituitary–gonads axis, leading to downstream inhibitory and stimulatory effects on gonads. However, the mechanisms are not fully understood. In this study, we provide novel data demonstrating the stimulatory effects of cortisol on spermatogenesis using an ex vivo organ culture system. The results revealed that cortisol treatment did not modulate basal androgen production, but it influenced transcript levels of a selected number of genes involved in the zebrafish testicular function ar (androgen receptor), star (steroidogenic acute regulatory), cyp17a1 (17α-hydroxylase/17,20 lyase/17,20 desmolase), cyp11a2 (cytochrome P450, family 11, subfamily A, polypeptide 2), hsd11b2 (11-beta hydroxysteroid dehydrogenase), cyp2k22 (cytochrome P450, family 2, subfamily K, polypeptide 22), fkbp5 (FKBP prolyl isomerase 5), grα (glucocorticoid receptor alpha), and grβ (glucocorticoid receptor beta) in a short-term culture. We also showed that cortisol stimulates spermatogonial proliferation and differentiation in an androgen independent manner as well as promoting meiosis and spermiogenesis by increasing the number of spermatozoa in the testes. Moreover, we demonstrated that concomitant treatment with RU 486, a potent glucocorticoid receptor (Gr) antagonist, did not affect the cortisol effects on spermatogonial differentiation but blocked the induced effects on meiosis and spermiogenesis. Supporting the Gr-mediated effects, RU 486 nullified the cortisol-induced expression of sycp3l (synaptonemal complex protein 3), a marker for the meiotic prophase that encodes a component of the synaptonemal complex. This is consistent with in silico analysis that found 10 putative GREs (glucocorticoid response elements) upstream of the zebrafish sycp3l. Finally, we also showed that grα mRNA is expressed in Sertoli and Leydig cells, but also in several types of germ cells, including spermatogonia and spermatocytes. Altogether, this evidence indicates that cortisol exerts paracrine roles in the zebrafish testicular function and spermatogenesis, highlighting its effects on spermatogonial differentiation, meiosis, and spermiogenesis.

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Antagonistic regulation of spermatogonial differentiation in zebrafish (Danio rerio) by Igf3 and Amh

Cited by 49 publications

References 88 publications

Fsh stimulates Leydig cell Wnt5a production, enriching zebrafish type A spermatogonia

Fsh stimulates Leydig cell Wnt5a production, enriching zebrafish type A spermatogonia

Igf3 activates β-catenin signaling to stimulate spermatogonial differentiation in zebrafish

Cortisol Directly Stimulates Spermatogonial Differentiation, Meiosis, and Spermiogenesis in Zebrafish (Danio rerio) Testicular Explants

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