BMP6 Regulates Proliferation and Apoptosis of Human Sertoli Cells Via Smad2/3 and Cyclin D1 Pathway and DACH1 and TFAP2A Activation

Wang, Hong; Yuan, Quan; Sun, Min; Niu, Minghui; Wen, Lei; Fu, Han; Zhou, Fan; Chen, Zheng; Yao, Chencheng; Hou, Jingmei; Shen, Ruinan; Lin, Qisheng; Liu, Wenjie; Jia, Ruobing; Li, Zheng; He, Zuping

doi:10.1038/srep45298

Cited by 33 publications

(28 citation statements)

References 55 publications

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“…Bone morphogenetic protein 6 (BMP6) was reported to inhibit apoptosis and to influence the production of tight junction protein 1 (TJP1), GDNF, and KITLG in Sertoli cells [ 40 ]. Although we observed a downregulation of BMP6 , the expression levels of TJP1 , KITLG , and GDNF were not significantly (FDR>0.05) altered between the two groups.…”

Section: Discussionmentioning

confidence: 99%

Curative GnRHa treatment has an unexpected repressive effect on Sertoli cell specific genes

Gegenschatz‐Schmid¹,

Verkauskas²,

Demougin³

et al. 2018

Basic Clin. Androl.

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BackgroundFollicle stimulating hormone and testosterone stimulate Sertoli cells to support germ cell function and differentiation. During mini-puberty, when gonadotropin (GnRH) stimulates increases in plasma luteinizing hormone (LH) and testosterone levels, gonocytes are transformed into Ad spermatogonia. In cryptorchidism, impaired gonadotropin secretion during mini-puberty results in insufficient LH and testosterone secretion, impaired gonocyte transition to Ad spermatogonia, and perturbed Sertoli cell proliferation. Treatment with a gonadotropin-releasing hormone agonist (GnRHa/Buserelin) induced gonocytes to differentiate into Ad spermatogonia and rescued fertility. The present study evaluated the impact of low LH secretion on Sertoli cell function by comparing differential gene expression data between testes with low LH that lacked Ad spermatogonia (Ad-) and testes that completed mini-puberty (Ad+). Furthermore, we analyzed changes in the transcription of selected Sertoli cell specific genes in response to GnRHa treatment.ResultsAd- testes showed reduced expression of nine out of 40 selected Sertoli cell specific genes compared to Ad+ testes. GnRHa treatment repressed most of the Sertoli cell specific genes, including the inhibins, but it increased the expression of genes that regulate apoptosis (FASLG) and proliferation (GDNF).ConclusionsImpaired-minipuberty with decreased LH and testosterone levels affected Ad and Sertoli cell development through positive and negative regulation of morphoregulatory and apoptotic genes. GnRHa treatment had a repressive effect on most Sertoli cell specific genes, which suggested that Sertoli cells underwent a cellular rearrangement. We propose that gonadotropin-dependent increases in FASLG and GDNF expression drove Sertoli cell proliferation and germ cell self-renewal and supported the transition of gonocytes to Ad spermatogonia, independent of inhibins.

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Section: Discussionmentioning

confidence: 99%

Curative GnRHa treatment has an unexpected repressive effect on Sertoli cell specific genes

Gegenschatz‐Schmid¹,

Verkauskas²,

Demougin³

et al. 2018

Basic Clin. Androl.

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“…Despite it is well-studied the role of cyclin/cdk complexes in spermatogenesis, where they are involved in control of cell growth, differentiation, and apoptosis (Clement et al, 2015 ; Panigrahi et al, 2017 ; Wang et al, 2017 ), it is surprising that it could be possible to hypothesize an active role of these molecules in capacitation. To our knowledge, so far, there is a limited number of studies on their possible involvement in physiology of mature male gametes.…”

Section: Discussionmentioning

confidence: 99%

Aminopurvalanol A, a Potent, Selective, and Cell Permeable Inhibitor of Cyclins/Cdk Complexes, Causes the Reduction of in Vitro Fertilizing Ability of Boar Spermatozoa, by Negatively Affecting the Capacitation-Dependent Actin Polymerization

Bernabò¹,

Valbonetti²,

Greco³

et al. 2017

Front. Physiol.

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The adoption of high-througput technologies demonstrated that in mature spermatozoa are present proteins that are thought to be not present or active in sperm cells, such as those involved in control of cell cycle. Here, by using an in silico approach based on the application of networks theory, we found that Cyclins/Cdk complexes could play a central role in signal transduction active during capacitation. Then, we tested this hypothesis in the vitro model. With this approach, spermatozoa were incubated under capacitating conditions in control conditions (CTRL) or in the presence of Aminopurvalanol A a potent, selective and cell permeable inhibitor of Cyclins/Cdk complexes at different concentrations (2, 10, and 20 μM). We found that this treatment caused dose-dependent inhibition of sperm fertilizing ability. We attribute this event to the loss of acrosome integrity due to the inhibition of physiological capacitation-dependent actin polymerization, rather than to a detrimental effect on membrane lipid remodeling or on other signaling pathways such as tubulin reorganization or MAPKs activation. In our opinion, these data could revamp the knowledge on biochemistry of sperm capacitation and could suggest new perspectives in studying male infertility.

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“…However, the contribution of Smad1/5 pathway against the ID2/3 pathway in BMP4-induced SCs proliferation enhancement was not evaluated in their research. This problem also exists in the study of BMP6, particularly, whether the Smad2/3 signaling pathway directly mediates the BMP6-induced proliferation, and increased levels of SCF and Glial cellderived neurotrophic factor (GDNF) in human SCs 71 .…”

Section: Ratmentioning

confidence: 99%

Multiple signaling pathways in Sertoli cells: recent findings in spermatogenesis

2019

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The functions of Sertoli cells in spermatogenesis have attracted much more attention recently. Normal spermatogenesis depends on Sertoli cells, mainly due to their influence on nutrient supply, maintenance of cell junctions, and support for germ cells’ mitosis and meiosis. Accumulating evidence in the past decade has highlighted the dominant functions of the MAPK, AMPK, and TGF-β/Smad signaling pathways during spermatogenesis. Among these pathways, the MAPK signaling pathway regulates dynamics of tight junctions and adherens junctions, proliferation and meiosis of germ cells, proliferation and lactate production of Sertoli cells; the AMPK and the TGF-β/Smad signaling pathways both affect dynamics of tight junctions and adherens junctions, as well as the proliferation of Sertoli cells. The AMPK signaling pathway also regulates lactate supply. These signaling pathways combine to form a complex regulatory network for spermatogenesis. In testicular tumors or infertile patients, the activities of these signaling pathways in Sertoli cells are abnormal. Clarifying the mechanisms of signaling pathways in Sertoli cells on spermatogenesis provides new insights into the physiological functions of Sertoli cells in male reproduction, and also serves as a pre-requisite to identify potential therapeutic targets in abnormal spermatogenesis including testicular tumor and male infertility.

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BMP6 Regulates Proliferation and Apoptosis of Human Sertoli Cells Via Smad2/3 and Cyclin D1 Pathway and DACH1 and TFAP2A Activation

Cited by 33 publications

References 55 publications

Curative GnRHa treatment has an unexpected repressive effect on Sertoli cell specific genes

Curative GnRHa treatment has an unexpected repressive effect on Sertoli cell specific genes

Aminopurvalanol A, a Potent, Selective, and Cell Permeable Inhibitor of Cyclins/Cdk Complexes, Causes the Reduction of in Vitro Fertilizing Ability of Boar Spermatozoa, by Negatively Affecting the Capacitation-Dependent Actin Polymerization

Multiple signaling pathways in Sertoli cells: recent findings in spermatogenesis

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