hnRNPU in Sertoli cells cooperates with WT1 and is essential for testicular development by modulating transcriptional factors Sox8/9.
hnRNPU in Sertoli cells cooperates with WT1 and is essential for testicular development by modulating transcriptional factors Sox8/9.
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支持细胞中的 hnRNPU 与 WT1 合作，通过调节转录因子 Sox8/9 对睾丸发育至关重要
作者：
Wen Y;Ma X;Wang X;Wang F;Dong J;Wu Y;Lv C;Liu K;Zhang Y;Zhang Z;Yuan S
背景资料：支持细胞是分化性腺中睾丸命运的重要调节因子，然而，其调节青春期前睾丸发育的作用和潜在的分子机制知之甚少。虽然支持细胞的发育和功能的几个关键的调节因素已被确定，确定外源性因素，调节生殖细胞的增殖和迁移过程中新生儿睾丸发育仍然在很大程度上是未知的。研究方法：我们在小鼠中使用支持细胞特异性条件敲除策略（Cre/Loxp），并进行分子生物学分析（荧光素酶测定、ChIP-qPCR、RNA-Seq等）。在体外和体内研究hnRNPU在支持细胞中对青春期前睾丸发育的调节作用。结果如下：我们确定了一个共转录因子，hnRNPU，这是高度表达的小鼠和人类支持细胞和新生儿支持细胞和青春期前睾丸发育所需的。小鼠支持细胞中hnRNPU的条件性敲除导致严重的睾丸萎缩和雄性不育，其特征在于支持细胞和生殖细胞的快速消耗以及青春期前睾丸发育期间精原细胞增殖和迁移的失败。在分子水平上，我们发现hnRNPU与两个支持细胞标志物WT 1和SOX 9相互作用，并通过直接结合到支持细胞的启动子区域来增强两个转录因子Sox 8和Sox 9在支持细胞中的表达。进一步的RNA-Seq和生物信息学分析显示，支持细胞和生殖细胞命运控制所必需的关键基因的转录组范围，如生物粘附，增殖和迁移，在支持细胞特异性hnRNPU突变体睾丸中失调。结论：我们的研究结果表明hnRNPU在支持细胞中对青春期前睾丸发育和睾丸微环境维持的重要作用，并为我们理解男性不育治疗提供了新的见解。
Background: Sertoli cells are essential regulators of testicular fate in the differentiating gonad; however, its role and underlying molecular mechanism of regulating testicular development in prepubertal testes are poorly understood. Although several critical regulatory factors of Sertoli cell development and function have been identified, identifying extrinsic factors that regulate gonocyte proliferation and migration processes during neonatal testis development remains largely unknown. Methods: We used the Sertoli cell-specific conditional knockout strategy (Cre/Loxp) in mice and molecular biological analyses (Luciferase assay, ChIP-qPCR, RNA-Seq, etc.) in vitro and in vivo to study the physiological roles of hnRNPU in Sertoli cells on regulating testicular development in prepubertal testes. Results: We identified a co-transcription factor, hnRNPU, which is highly expressed in mouse and human Sertoli cells and required for neonatal Sertoli cell and pre-pubertal testicular development. Conditional knockout of hnRNPU in murine Sertoli cells leads to severe testicular atrophy and male sterility, characterized by rapid depletion of both Sertoli cells and germ cells and failure of spermatogonia proliferation and migration during pre-pubertal testicular development. At molecular levels, we found that hnRNPU interacts with two Sertoli cell markers WT1 and SOX9, and enhances the expression of two transcriptional factors, Sox8 and Sox9, in Sertoli cells by directly binding to their promoter regions. Further RNA-Seq and bioinformatics analyses revealed the transcriptome-wide of key genes essential for Sertoli cell and germ cell fate control, such as biological adhesion, proliferation and migration, were deregulated in Sertoli cell-specific hnRNPU mutant testes. Conclusion: Our findings demonstrate an essential role of hnRNPU in Sertoli cells for prepubertal testicular development and testis microenvironment maintenance and define a new insight for our understanding of male infertility therapy.
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影响因子：
2.5
作者：
Combes, Alexander N.;Lesieur, Emmanuelle;Harley, Vincent R.;Sinclair, Andrew H.;Little, Melissa H.;Wilhelm, Dagmar;Koopman, Peter
通讯作者：
Koopman, Peter
DOI：
10.1073/pnas.0600994103
发表时间：
2006-08-08
影响因子：
11.1
作者：
Gao, Fei;Maiti, Sourindra;Huff, Vicki
通讯作者：
Huff, Vicki
影响因子：
3.6
作者：
Holsberger, DR;Buchold, GM;Cooke, PS
通讯作者：
Cooke, PS
影响因子：
4.6
作者：
Everaert C;Luypaert M;Maag JLV;Cheng QX;Dinger ME;Hellemans J;Mestdagh P
通讯作者：
Mestdagh P
肾母细胞瘤基因 Wt1 通过调节 Col4a1 和 Col4a2 的表达来维持睾丸索完整性
影响因子：
3.6
作者：
Chen, Su-Ren;Chen, Min;Liu, Yi-Xun
通讯作者：
Liu, Yi-Xun