Wt1 Is Involved in Leydig Cell Steroid Hormone Biosynthesis by Regulating Paracrine Factor Expression in Mice1
Wt1 Is Involved in Leydig Cell Steroid Hormone Biosynthesis by Regulating Paracrine Factor Expression in Mice1
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DOI：
10.1095/biolreprod.113.114702
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发表时间：
2014-04-01
影响因子：
3.6
通讯作者：
Gao, Fei
中科院分区：
文献类型：
--
作者：
Chen, Min;Wang, Xiaona;Gao, Fei
Wilms肿瘤基因Wt 1在睾丸支持细胞中大量表达。我们最近的研究表明Wt 1通过调节支持细胞极性参与精子发生。在本研究中，我们发现Wt 1也是Leydig细胞类固醇合成所必需的，并且Wt 1基因的缺失导致睾酮合成的缺陷和类固醇合成基因表达的下调，包括细胞色素P450侧链切割（P450 SCC）、类固醇合成急性调节蛋白（星星）、3 β-羟基类固醇脱氢酶I（3 β-hydroxysteroiddehydrogenase I，4 β-hydrosteroiddehydrogenase I，4 β-hydrosteroidase I，4 β-hydro（3 β-HSD）和细胞色素P450 17 A1（Cyp 17 a1）。三苯氧胺诱导后，Wt 1（-/flox）; Cre-ERTM睾丸中LHR的表达显著降低，而血清中黄体生成素水平无变化。进一步的研究表明，沙漠刺猬（Dhh）的表达在支持细胞中受Wt 1的调控，其表达在Wt 1缺陷的睾丸中显着降低。在体外研究表明，在Wt 1缺陷睾丸外植体中的睾酮产生的缺陷和几个类固醇基因的表达减少部分获救的smoothened激动剂（SAG），刺猬途径激动剂。这些结果表明，Wt 1是最有可能参与间质细胞类固醇激素的表达调控曲细精管的旁分泌因子。DHH可能在这个过程中发挥了重要作用，但我们不能排除Leydig细胞类固醇生成也需要其他因素的可能性。Wt 1的缺失导致旁分泌因子的下调，这反过来又导致类固醇生成酶表达的减少，并减少睾丸间质细胞中睾酮的产生。本研究结果进一步证实了支持细胞和间质细胞之间的相互作用在间质细胞类固醇合成中具有重要作用。
Wilms tumor gene, Wt1, is abundantly expressed in testis Sertoli cells. Our recent study demonstrated that Wt1 is involved in spermatogenesis by regulating Sertoli cell polarity. In the present study, we found that Wt1 is also required for steroidogenesis in Leydig cells and that deletion of the Wt1 gene resulted in defects in testosterone biosynthesis and downregulation of steroidogenic gene expression, including cytochrome P450 side-chain cleavage (P450scc), steroidogenic acute regulatory protein (StAR), 3beta-hydroxysteroid dehydrogenase I (3beta-HSD), and cytochrome P450 17A1 (Cyp17a1). The expression of LHR was significantly decreased in Wt1(-/flox); Cre-ERTM testes after tamoxifen induction, whereas the luteinizing hormone level in serum was unchanged. Further studies revealed that desert hedgehog (Dhh) expression was regulated by Wt1 in Sertoli cells and that its expression was significantly reduced in Wt1-deficient testes. In vitro study demonstrated that the defect in testosterone production and decreased expression of several steroidogenic genes in Wt1-deficient testis explants was partially rescued by smoothened agonist (SAG), a hedgehog pathway agonist. These results indicate that Wt1 is most likely involved in Leydig cell steroidogenesis by regulating the expression of paracrine factors in seminiferous tubules. Dhh probably had important roles in this process, but we could not exclude the possibility that other factors were also required for Leydig cell steroidogenesis. Loss of Wt1 leads to downregulation of paracrine factors, which in turn causes a decrease in steroidogenic enzyme expression and reduces testosterone production in Leydig cells. The results of this study further confirm that the cross talk between Sertoli cells and Leydig cells has important roles in Leydig cell steroidogenesis.