Mutation of the mouse hepatocyte nuclear factor forkhead homologue 4 gene results in an absence of cilia and random left-right asymmetry
Mutation of the mouse hepatocyte nuclear factor forkhead homologue 4 gene results in an absence of cilia and random left-right asymmetry
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DOI：
10.1172/jci4786
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发表时间：
1998-09-15
影响因子：
15.9
通讯作者：
Hackett, BP
中科院分区：
文献类型：
--
作者：
Chen, JC;Knowles, HJ;Hackett, BP
翼状螺旋转录因子在细胞分化和细胞特异性基因表达中起重要作用。为了确定翼螺旋因子肝细胞核因子/叉头同源物（HFH）-4的作用，在小鼠hfh-4基因中产生靶向突变。通过RNA印迹分析、原位杂交或RT-PCR检测，在hflt-4（-/-）小鼠中未检测到HFH-4的表达。注意到HFH-4（-/-）小鼠具有与左右不对称性的随机测定一致的器官位置异常。此外，在hfh-4（-/-）小鼠中观察到纤毛完全缺失。因此hfh-4基因对于左右不对称的非随机决定和纤毛细胞的发育是必不可少的。纯合子突变小鼠也表现出产前和产后生长障碍，围产期死亡，在某些情况下，脑积水。RT-PCR显示HFH-4（-/-）小鼠胚胎肺中缺乏左右动力蛋白（lrd）表达，表明HFH-4可能通过调节动力蛋白家族基因成员的表达而起作用。hfh-4（-/-）小鼠的纤毛发育和器官位置异常与人类先天性综合征（如Kartagener综合征）中观察到的异常相似。因此，hfh-4的靶向突变为阐明调节纤毛发育和确定左右不对称性的机制提供了模型。
Winged helix transcription factors play important roles in cellular differentiation and cell-specific gene expression. To define the role of the winged helix factor hepatocyte nuclear factor/forkhead homologue (HFH)-4, a targeted mutation was created in the mouse hfh-4 gene. No expression of HFH-4 was detected in hflt-4(-/-) mice by RNA blot analysis, in situ hybridization, or RT-PCR. hfh-4(-/-) mice were noted to have abnormalities of organ situs consistent with random determination of left-right asymmetry. In addition, a complete absence of cilia was noted in hfh-4(-/-) mice. The hfh-4 gene is thus essential for nonrandom determination of left-right asymmetry and development of ciliated cells. Homozygous mutant mice also exhibited prenatal and postnatal growth failure, perinatal lethality and, in some cases, hydrocephalus. RT-PCR revealed an absence of left-right dynein (lrd) expression in the embryonic lungs of hfh-4(-/-) mice, suggesting that HFH-4 may act by regulating expression of members of the dynein family of genes. The abnormalities in ciliary development and organ situs in hfh-4(-/-) mice are similar to those observed in human congenital syndromes such as Kartagener syndrome. Targeted mutation of hfh-4 thus provides a model for elucidating the mechanisms regulating ciliary development and determination of left-right asymmetry.