Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification
Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification
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DOI：
10.1038/ng1684
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发表时间：
2006-01-01
期刊：
影响因子：
30.8
通讯作者：
Franco, B
中科院分区：
文献类型：
--
作者：
Ferrante, MI;Zullo, A;Franco, B
口腔-面部-手指I型综合征(OMIM 311200)是一种人类发育障碍；受影响的个体有头面部和手指畸形，在15%的病例中有多囊肾(1，2)。这种疾病是作为一种X连锁显性男性致死性状遗传的。使用Cre-loxP系统，我们产生了缺乏Ofd1的基因敲除动物，并复制了疾病的主要特征，尽管病情加重，可能是由于人类和小鼠之间X失活模式的差异。我们在突变的雄性胚胎中发现了左右轴规范的失败，超微结构分析显示胚节中缺少纤毛。在杂合子女性的囊性肾中纤毛的形成是有缺陷的，暗示纤毛发生是囊性发育的一个机制。此外，我们还发现，在缺乏Ofd1的小鼠的肢芽中，神经管的图案受损，5‘Hoxa和Hoxd基因的表达发生了变化，这表明Ofd1的作用可能超出了初级纤毛的组织和组装。
The oral-facial-digital type I (OFD1) syndrome ( OMIM 311200) is a human developmental disorder; affected individuals have craniofacial and digital abnormalities and, in 15% of cases, polycystic kidney(1,2). The disease is inherited as an X-linked dominant male-lethal trait. Using a Cre-loxP system, we generated knockout animals lacking Ofd1 and reproduced the main features of the disease, albeit with increased severity, possibly owing to differences of X inactivation patterns between human and mouse. We found failure of left-right axis specification in mutant male embryos, and ultrastructural analysis showed a lack of cilia in the embryonic node. Formation of cilia was defective in cystic kidneys from heterozygous females, implicating ciliogenesis as a mechanism underlying cyst development. In addition, we found impaired patterning of the neural tube and altered expression of the 5' Hoxa and Hoxd genes in the limb buds of mice lacking Ofd1, suggesting that Ofd1 could have a role beyond primary cilium organization and assembly.