The Wilms Tumor Gene, Wt1, Is Critical for Mouse Spermatogenesis via Regulation of Sertoli Cell Polarity and Is Associated with Non-Obstructive Azoospermia in Humans

Wang, Xiao Na; Li, Ze Song; Ren, Yu; Jiang, Tao; Wang, Ya Qing; Chen, Min; Zhang, Jun; Hao, Jian; Wang, Yan Bo; Sha, Ri Na; Huang, Yi; Liu, Xiao; Hu, Jing Chu; Sun, Guang; Li, Hong Gang; Xiong, Cheng Liang; Xie, Jun; Jiang, Zhi; Lei, Ting; Wang, Jun; Wang, Jian; Huff, Vicki; Gui, Yao Ting; Gao, Fei

doi:10.1371/journal.pgen.1003645

Cited by 119 publications

(96 citation statements)

References 57 publications

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“…To trace the origin of 3β-HSD-positive cells in Wt1-deficient gonads, a WT1 and 3β-HSD double staining experiment was performed. Our previous studies demonstrated that although the small truncated WT1 protein remaining after the deletion of two exons from the Wt1 flox allele had lost its function, it was still recognized by the antibody used in this study and could be used to trace the Wt1 mutant cells (Gao et al, 2006;Hu et al, 2011;Wang et al, 2013). We found that most 3β-HSD-positive cells were also positive for WT1 (Fig.…”

Section: Wt1mentioning

confidence: 54%

Wt1 directs the lineage specification of sertoli and granulosa cells by repressing Sf1 expression

et al. 2016

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Supporting cells (Sertoli and granulosa) and steroidogenic cells (Leydig and theca-interstitium) are two major somatic cell types in mammalian gonads, but the mechanisms that control their differentiation during gonad development remain elusive. In this study, we found that deletion of Wt1 in the ovary after sex determination caused ectopic development of steroidogenic cells at the embryonic stage. Furthermore, differentiation of both Sertoli and granulosa cells was blocked when Wt1 was deleted before sex determination and most genital ridge somatic cells differentiated into steroidogenic cells in both male and female gonads. Further studies revealed that WT1 repressed Sf1 expression by directly binding to the Sf1 promoter region, and the repressive function was completely abolished when WT1 binding sites were mutated. This study demonstrates that Wt1 is required for the lineage specification of both Sertoli and granulosa cells by repressing Sf1 expression. Without Wt1, the expression of Sf1 was upregulated and the somatic cells differentiated into steroidogenic cells instead of supporting cells. Our study uncovers a novel mechanism of somatic cell differentiation during gonad development.

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Section: Wt1mentioning

confidence: 54%

Wt1 directs the lineage specification of sertoli and granulosa cells by repressing Sf1 expression

et al. 2016

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“…However, no WT1 signal was detected in the tumor cells from double KO mice (Fig. 1F), despite the fact that it has been demonstrated that the small truncated WT1 protein remaining after the deletion of two exons from the Wt1 flox allele is recognized by the antibody used in this study and can be used to trace Wt1 mutant Sertoli cells (13,16). Surprisingly, the Leydig cell-specific marker genes 3β-HSD and P450SCC were abundantly expressed in double KO tumor cells ( (Fig.…”

Section: Resultsmentioning

confidence: 72%

Reprogramming of Sertoli cells to fetal-like Leydig cells by Wt1 ablation

Zhang

Chen

Wen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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.

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“…NOA is a heterogeneous disorder caused by complex genetic and environmental factors. Hereditary changes, including chromosome abnormalities and gene mutations, have been implicated in NOA (4)(5)(6); however, the etiology of this disease remains largely unclear.…”

mentioning

confidence: 99%

Major spliceosome defects cause male infertility and are associated with nonobstructive azoospermia in humans

Sun

Wen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Processing of pre-mRNA into mRNA is an important regulatory mechanism in eukaryotes that is mediated by the spliceosome, a huge and dynamic ribonucleoprotein complex. Splicing defects are implicated in a spectrum of human disease, but the underlying mechanistic links remain largely unresolved. Using a genome-wide association approach, we have recently identified single nucleotide polymorphisms in humans that associate with nonobstructive azoospermia (NOA), a common cause of male infertility. Here, using genetic manipulation of corresponding candidate loci in Drosophila, we show that the spliceosome component SNRPA1/U2A is essential for male fertility. Loss of U2A in germ cells of the Drosophila testis does not affect germline stem cells, but does result in the accumulation of mitotic spermatogonia that fail to differentiate into spermatocytes and mature sperm. Lack of U2A causes insufficient splicing of mRNAs required for the transition of germ cells from proliferation to differentiation. We show that germ cellspecific disruption of other components of the major spliceosome manifests with the same phenotype, demonstrating that mRNA processing is required for the differentiation of spermatogonia. This requirement is conserved, and expression of human SNRPA1 fully restores spermatogenesis in U2A mutant flies. We further report that several missense mutations in human SNRPA1 that inhibit the assembly of the major spliceosome dominantly disrupt spermatogonial differentiation in Drosophila. Collectively, our findings uncover a conserved and specific requirement for the major spliceosome during the transition from spermatogonial proliferation to differentiation in the male testis, suggesting that spliceosome defects affecting the differentiation of human spermatogonia contribute to NOA.

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The Wilms Tumor Gene, Wt1, Is Critical for Mouse Spermatogenesis via Regulation of Sertoli Cell Polarity and Is Associated with Non-Obstructive Azoospermia in Humans

Cited by 119 publications

References 57 publications

Wt1 directs the lineage specification of sertoli and granulosa cells by repressing Sf1 expression

Wt1 directs the lineage specification of sertoli and granulosa cells by repressing Sf1 expression

Reprogramming of Sertoli cells to fetal-like Leydig cells by Wt1 ablation

Major spliceosome defects cause male infertility and are associated with nonobstructive azoospermia in humans

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