The Wilms tumor gene, Wt1, is required for Sox9 expression and maintenance of tubular architecture in the developing testis
The Wilms tumor gene, Wt1, is required for Sox9 expression and maintenance of tubular architecture in the developing testis
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DOI：
10.1073/pnas.0600994103
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发表时间：
2006-08-08
影响因子：
11.1
通讯作者：
Huff, Vicki
中科院分区：
文献类型：
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作者：
Gao, Fei;Maiti, Sourindra;Huff, Vicki
转录因子和肿瘤抑制基因WT1的突变导致人类一系列泌尿生殖系统异常，包括46，XY性腺发育不全，表明WT1在性别决定中起着关键作用。然而，由于敲除小鼠Wt1导致生殖嵴凋亡，因此尚不清楚Wt1是否是性别决定最初步骤后睾丸发育所需的。为了解决这个问题，我们产生了一个小鼠品系携带Wt1条件性基因敲除等位基因和消融Wt1功能，特别是在胚胎第14.5天，睾丸测定后几天的支持细胞。Wt1基因敲除导致发育中的生精小管破坏，随后支持细胞和生殖细胞逐渐丧失，因此出生后突变睾丸几乎完全缺乏这些细胞类型，严重发育不良。因此，Wt1对于发育中的睾丸中支持细胞和曲细精管的维持是必不可少的。特别值得注意的是，睾丸决定基因Sox 9在突变体支持细胞中的表达在Wt1消融后的胚胎第14.5天关闭，这表明Wt1在Sry表达停止后直接或间接地调节Sox 9。我们的数据，沿着与以前的工作证明了Wt1在性腺发育的早期阶段的作用，因此表明，Wt1是必不可少的在睾丸发育的多个步骤。
Mutation of the transcription factor and tumor suppressor gene WT1 results in a range of genitourinary anomalies in humans, including 46,XY gonadal dysgenesis, indicating that WT1 plays a critical role in sex determination. However, because knockout of Wt1 in mice results in apoptosis of the genital ridge, it is unknown whether WT1 is required for testis development after the initial steps of sex determination. To address this question, we generated a mouse strain carrying a Wt1 conditional knockout allele and ablated Wt1 function specifically in Sertoli cells by embryonic day 14.5, several days after testis determination. Wt1 knockout resulted in disruption of developing seminiferous tubules and subsequent progressive loss of Sertoli cells and germ cells such that postnatal mutant testes were almost completely devoid of these cell types and were severely hypoplastic. Thus, Wt1 is essential for the maintenance of Sertoli cells and seminiferous tubules in the developing testes. Of particular note, expression of the testis-determining gene Sox9 in mutant Sertoli cells was turned off at embryonic day 14.5 after Wt1 ablation, suggesting that WT1 regulates Sox9, either directly or indirectly, after Sry expression ceases. Our data, along with previous work demonstrating the role of Wt1 at early stages of gonadal development, thus indicate that Wt1 is essential at multiple steps in testicular development.