A novel isoform of Vinexin, Vinexin γ, regulates Sox9 gene expression through activation of MAPK cascade in mouse fetal gonad
A novel isoform of Vinexin, Vinexin γ, regulates Sox9 gene expression through activation of MAPK cascade in mouse fetal gonad
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DOI：
10.1111/j.1365-2443.2005.00844.x
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发表时间：
2005-05
期刊：
影响因子：
2.1
通讯作者：
M. Matsuyama;H. Mizusaki;A. Shimono;T. Mukai;K. Okumura;K. Abe;K. Shimada;K. Morohashi
中科院分区：
文献类型：
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作者：
M. Matsuyama;H. Mizusaki;A. Shimono;T. Mukai;K. Okumura;K. Abe;K. Shimada;K. Morohashi
最近的功能丧失和功能获得研究表明，转录因子Sox9是睾丸形成所必需的，它通过调控Sertoli细胞的分化，从而调节Sertoli标记基因的转录。在本研究中，我们发现了一种新的Vinexin亚型，它在不同性别阶段的胎儿性腺的体细胞中表达，但在生殖细胞中不表达。性别确定后，这种表达在睾丸支持细胞中继续表达。免疫组织化学分析表明，Vinexinγ定位于细胞质中。对C3H10T1/2细胞的功能研究表明，Vinexinγ作为支架蛋白，通过与c-Raf和ERK的相互作用来激活MEKs和ERKs。最终，Venexinγ诱导了Sox9的转录。当用特定的MEK抑制剂U0126处理细胞时，这种上调Sox9表达的作用消失。为了确定Vinexinγ在性腺形成过程中的作用，该基因被定向突变打乱。小鼠的表型显示，在Vinexinγ−/-XY性腺中ERK活性降低，Sox9表达下调。因此，Vinexinγ可能通过调节小鼠胎儿性腺中的丝裂原活化蛋白激酶级联来调控Sox9基因的表达。
Recent loss‐of‐function and gain‐of‐function studies have revealed that transcription factor Sox9 is required for testis formation by governing Sertoli cell differentiation, and thereafter regulating transcription of Sertoli marker genes. In the present study, we identified a novel isoform of Vinexin, which is expressed in somatic cells but not germ cells of sexually indifferent stages of fetal gonads. After the sex is determined, the expression continues in testicular Sertoli cells. Immunohistochemical analyses with a specific antibody to Vinexin indicated that Vinexin γ is localized in the cytoplasm. Functional studies with C3H10T1/2 cells showed that Vinexin γ acted as a scaffold protein to activate MEK and ERK through interaction with c‐Raf and ERK. Ultimately, Sox9 transcription was induced by Vinexin γ. This up‐regulation of Sox9 expression disappeared when the cells were treated with a specific MEK inhibitor, U0126. To determine the role of Vinexin γ during gonad formation, the gene was disrupted by targeted mutagenesis. The phenotype displayed by the mice indicated that ERK activation was decreased in the Vinexin γ−/– XY gonads, and Sox9 expression was down‐regulated. Thus, Vinexin γ seems to be implicated in regulation of Sox9 gene expression by modulating MAPK cascade in mouse fetal gonads.