Abnormal development of urogenital organs in Dlgh1-deficient mice
Abnormal development of urogenital organs in Dlgh1-deficient mice
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DOI：
10.1242/dev.02830
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发表时间：
2007-05-01
期刊：
影响因子：
4.6
通讯作者：
Senda, Takao
中科院分区：
文献类型：
--
作者：
Iizuka-Kogo, Akiko;Ishidao, Takefumi;Senda, Takao
Dlgh1（discslarge 同源物 1）是果蝇肿瘤抑制因子 Discslarge 1 的哺乳动物同源物，并且是膜相关鸟苷酸激酶 (MAGUK) 支架蛋白的成员，该支架蛋白包含三个 PSD-95/Dlg/ZO-1 (PDZ) 结构域。大圆盘 1 参与果蝇发育过程中的上皮极化和细胞间粘附复合物的形成。然而，Dlgh1 在哺乳动物发育过程中的功能仍有待阐明。我们培育了 Dlgh1 敲除小鼠，发现纯合 Dlgh1 敲除小鼠的肾脏和泌尿生殖器官出现了各种异常。肾脏和输尿管发育不全，输尿管下端异位。此外，分别源自缪勒管和沃尔夫管下部的阴道和精囊也不存在。出乎意料的是，发育中的输尿管中 Dlgh1 功能的丧失并没有破坏细胞-细胞连接复合物，但确实损害了上皮细胞的增殖。这些结果表明 Dlgh1 在哺乳动物发育过程中调节上皮导管形成和形态发生中具有新作用。尽管先天性阴道缺失与其他不同苗勒氏管异常相关的人类已有报道，但其机制尚未阐明。我们的发现可能有助于更好地理解此类异常。
Dlgh1 (discs large homolog 1) is a mammalian homolog of the Drosophila tumor suppressor Discs large 1, and is a member of the membrane-associated guanylate kinase (MAGUK) scaffolding proteins that contain three PSD-95/Dlg/ZO-1 (PDZ) domains. Discs large 1 is involved in epithelial polarization and cell-cell adhesion complex formation during Drosophila development. However, the functions of Dlgh1 during mammalian development remain to be elucidated. We generated Dlgh1-knockout mice and found that homozygous Dlgh1-knockout mice developed various abnormalities in their renal and urogenital organs. The kidneys and ureters were hypoplastic and the lower ends of the ureters were ectopic. In addition, the vagina and seminal vesicle, which are derived from the lower part of the Mullerian and Wolffian duct, respectively, were absent. Unexpectedly, loss of Dlgh1 function in the developing ureters did not disrupt cell-cell junctional complexes, but did impair cellular proliferation in the epithelium. These results suggest a novel role for Dlgh1 in regulating epithelial duct formation and morphogenesis during mammalian development. Although congenital absence of the vagina associated with other variable Mullerian duct abnormalities has been reported in humans, its mechanism has not yet been clarified. Our findings might contribute to a better understanding of such abnormalities.