Zhang Lianjun, Chen Min, Wen Qing, Li Yaqiong, Wang Yaqing, Wang Yanbo, Qin Yan, Cui Xiuhong, Yang Lin, Huff Vicki, Gao Fei
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Science, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100101, China;
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Science, Beijing 100101, China;
Proc Natl Acad Sci U S A. 2015 Mar 31;112(13):4003-8. doi: 10.1073/pnas.1422371112. Epub 2015 Mar 16.
Sertoli and Leydig cells, the two major somatic cell types in the testis, have different morphologies and functions. Both are essential for gonad development and spermatogenesis. However, whether these cells are derived from the same progenitor cells and the mechanism regulating the differentiation between these two cell types during gonad development remains unclear. A previous study showed that overactivation of Ctnnb1 (cadherin-associated protein, beta 1) in Sertoli cells resulted in Sertoli cell tumors. Surprisingly, in the present study, we found that simultaneous deletion of Wilms' Tumor Gene 1 (Wt1) and overactivation of Ctnnb1 in Sertoli cells led to Leydig cell-like tumor development. Lineage tracing experiments revealed that the Leydig-like tumor cells were derived from Sertoli cells. Further studies confirmed that Wt1 is required for the maintenance of the Sertoli cell lineage and that deletion of Wt1 resulted in the reprogramming of Sertoli cells to Leydig cells. Consistent with this interpretation, overexpression of Wt1 in Leydig cells led to the up-regulation of Sertoli cell-specific gene expression and the down-regulation of steroidogenic gene expression. These results demonstrate that the distinction between Sertoli cells and Leydig cells is regulated by Wt1, implying that these two cell types most likely originate from the same progenitor cells. This study thus provides a novel concept for somatic cell fate determination in testis development that may also represent an etiology of male infertility in human patients.
睾丸中的两种主要体细胞类型——支持细胞和间质细胞，具有不同的形态和功能。它们对于性腺发育和精子发生均至关重要。然而，这些细胞是否源自相同的祖细胞，以及在性腺发育过程中调节这两种细胞类型之间分化的机制仍不清楚。先前的一项研究表明，支持细胞中Ctnnb1（钙黏蛋白相关蛋白，β1）的过度激活会导致支持细胞瘤。令人惊讶的是，在本研究中，我们发现支持细胞中Wilms肿瘤基因1（Wt1）的同时缺失和Ctnnb1的过度激活会导致间质样细胞瘤的发生。谱系追踪实验表明，间质样肿瘤细胞源自支持细胞。进一步的研究证实，Wt1是维持支持细胞谱系所必需的，Wt1的缺失导致支持细胞重编程为间质细胞。与此解释一致，间质细胞中Wt1的过表达导致支持细胞特异性基因表达上调和类固醇生成基因表达下调。这些结果表明，支持细胞和间质细胞之间的差异受Wt1调节这意味着这两种细胞类型很可能源自相同的祖细胞。因此，本研究为睾丸发育中体细胞命运决定提供了一个新的概念，这也可能代表人类男性不育的一种病因。
