title: Reprogramming of Sertoli cells to fetal-like Leydig cells by Wt1 ablation.
abstract: 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.
authors.affiliation: 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;
authors.forename: Lianjun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Science, Beijing 100101, China;
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.affiliation: 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;
authors.forename: Qing
authors.initials: Q
authors.lastname: Wen
authors.affiliation: 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;
authors.forename: Yaqiong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China;
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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;
authors.forename: Yanbo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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;
authors.forename: Yan
authors.initials: Y
authors.lastname: Qin
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Science, Beijing 100101, China;
authors.forename: Xiuhong
authors.initials: X
authors.lastname: Cui
authors.affiliation: Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China;
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030; and Graduate Programs in Human Molecular Genetics and Genes and Development, University of Texas, Houston, TX 77030.
authors.forename: Vicki
authors.initials: V
authors.lastname: Huff
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Science, Beijing 100101, China; gaof@ioz.ac.cn.
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D007150:Immunohistochemistry; D007985:Leydig Cells / Q000166:cytology*; D008297:Male; D018345:Mice, Knockout; D012708:Sertoli Cells / Q000166:cytology*; D013737:Testis / Q000196:embryology / Q000254:growth & development*; D025721:WT1 Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics
chemical_list: C495267:CTNNB1 protein, mouse; D025721:WT1 Proteins; D051176:beta Catenin
keywords: Leydig cells; Sertoli cells; Wt1; transdifferentiation; β-catenin