The Luteinizing Hormone-Testosterone Pathway Regulates Mouse Spermatogonial Stem Cell Self-Renewal by Suppressing WNT5A Expression in Sertoli Cells.
The Luteinizing Hormone-Testosterone Pathway Regulates Mouse Spermatogonial Stem Cell Self-Renewal by Suppressing WNT5A Expression in Sertoli Cells.
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DOI：
10.1016/j.stemcr.2016.07.005
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发表时间：
2016-08-09
影响因子：
5.9
通讯作者：
Shinohara T
中科院分区：
文献类型：
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作者：
Tanaka T;Kanatsu-Shinohara M;Lei Z;Rao CV;Shinohara T
精子发生起源于精原干细胞的自我更新。先前的研究报道了促性腺垂体激素在SSC自我更新中的相互矛盾的作用。在这里，我们探讨了激素调节的作用，精原干细胞使用Fshb和Lhcgr敲除（KO）小鼠。虽然促卵泡激素（FSH）被认为是通过胶质细胞源性神经营养因子（GDNF）促进自我更新，但在SSCs及其微环境中没有发现异常。相反，精原干细胞在Lhcgr缺陷小鼠中富集。此外，移植到Lhcgr缺陷小鼠的野生型SSC显示出增强的自我更新。微阵列分析显示，Lhcgr缺陷的睾丸中支持细胞中WNT5A的表达增强，这显示出不成熟的表型。由于WNT5A通过抗雄激素治疗上调，因此支持细胞成熟需要促黄体生成素（LH）产生的睾酮。WNT5A在体外和体内均促进SSC活性。因此，FSH不负责GDNF调节，而LH通过睾酮抑制WNT5A来负调节SSC自我更新。Fshb和Lhcgr缺陷均不影响精原干细胞（SSC）在Lhcgr缺陷睾丸中的GDNF表达WNT5A在Lhcgr缺陷睾丸中上调WNT5A在体外和体内均增强SSC自我更新在这篇文章中，Shinohara和同事表明，GDNF，一种SSC的自我更新因子，不依赖于垂体激素信号。然而，SSC在Lhcgr突变小鼠中富集，这是由WNT5A上调引起的。WNT5A在体外和体内均促进SSC活性。因此，促黄体生成素通过抑制WNT5A来负调节SSC自我更新。
Spermatogenesis originates from self-renewal of spermatogonial stem cells (SSCs). Previous studies have reported conflicting roles of gonadotropic pituitary hormones in SSC self-renewal. Here, we explored the role of hormonal regulation of SSCs using Fshb and Lhcgr knockout (KO) mice. Although follicle-stimulating hormone (FSH) is thought to promote self-renewal by glial cell line-derived neurotrophic factor (GDNF), no abnormalities were found in SSCs and their microenvironment. In contrast, SSCs were enriched in Lhcgr-deficient mice. Moreover, wild-type SSCs transplanted into Lhcgr-deficient mice showed enhanced self-renewal. Microarray analysis revealed that Lhcgr-deficient testes have enhanced WNT5A expression in Sertoli cells, which showed an immature phenotype. Since WNT5A was upregulated by anti-androgen treatment, testosterone produced by luteinizing hormone (LH) is required for Sertoli cell maturation. WNT5A promoted SSC activity both in vitro and in vivo. Therefore, FSH is not responsible for GDNF regulation, while LH negatively regulates SSC self-renewal by suppressing WNT5A via testosterone. Neither Fshb nor Lhcgr deficiency influenced GDNF expression in testes Spermatogonial stem cells (SSCs) are enriched in Lhcgr-deficient testes WNT5A is upregulated in Lhcgr-deficient testes WNT5A enhances SSC self-renewal both in vitro and in vivo In this article, Shinohara and colleagues show that GDNF, a self-renewal factor for SSCs, is independent of pituitary hormone signaling. However, SSCs are enriched in Lhcgr mutant mice, which is caused by WNT5A upregulation. WNT5A promotes SSC activity both in vitro and in vivo. Therefore, luteinizing hormone negatively regulates SSC self-renewal by suppressing WNT5A.