The Cerebellin 4 Precursor Gene Is a Direct Target of SRY and SOX9 in Mice
The Cerebellin 4 Precursor Gene Is a Direct Target of SRY and SOX9 in Mice
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DOI：
10.1095/biolreprod.108.071480
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发表时间：
2009-06-01
影响因子：
3.6
通讯作者：
Wilhelm, Dagmar
中科院分区：
文献类型：
--
作者：
Bradford, Stephen T.;Hiramatsu, Ryuji;Wilhelm, Dagmar
在大多数哺乳动物中，SRY（Y染色体上的性别决定区）的表达启动睾丸的发育，从而决定个体的性别。然而，尽管SRY的关键作用，其作用机制仍然难以捉摸。其中一个重要的缺失部分是SRY调控基因的识别。在这项研究中，我们使用染色质免疫沉淀法来确定直接SRY靶基因。抗小鼠SRY抗体沉淀小脑蛋白4前体（Cbln4）转录起始位点上游7.5kb的区域，其编码分泌蛋白。Cbln4在发育中的性腺中的支持细胞中表达，其特征类似于含有基因9（Sox 9）的睾丸决定基因SRY盒。在Sox9表达减少的转基因XY小鼠胚胎中，Cbln4表达也减少，而在XX小鼠中Sox9的过表达导致Cbln4表达上调。最后，SRY在体内的异位上调导致Cbln4的异位表达。我们的研究结果表明，SRY和SOX 9都有助于在发育中的睾丸中Cbln4的男性特异性上调，并且他们确定了SRY的直接体内靶基因。
In most mammals, the expression of SRY (sex-determining region on the Y chromosome) initiates the development of testes, and thus determines the sex of the individual. However, despite the pivotal role of SRY, its mechanism of action remains elusive. One important missing piece of the puzzle is the identification of genes regulated by SRY. In this study we used chromatin immunoprecipitation to identify direct SRY target genes. Anti-mouse SRY antibody precipitated a region 7.5 kb upstream of the transcriptional start site of cerebellin 4 precursor (Cbln4), which encodes a secreted protein. Cbln4 is expressed in Sertoli cells in the developing gonad, with a profile mimicking that of the testis-determining gene SRY-box containing gene 9 (Sox9). In transgenic XY mouse embryos with reduced Sox9 expression, Cbln4 expression also was reduced, whereas overexpression of Sox9 in XX mice caused an upregulation of Cbln4 expression. Finally, ectopic upregulation of SRY in vivo resulted in ectopic expression of Cbln4. Our findings suggest that both SRY and SOX9 contribute to the male-specific upregulation of Cbln4 in the developing testis, and they identified a direct in vivo target gene of SRY.