Ciliogenesis and left-right axis defects in forkhead factor HFH-4-null mice
Ciliogenesis and left-right axis defects in forkhead factor HFH-4-null mice
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DOI：
10.1165/ajrcmb.23.1.4070
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发表时间：
2000-07-01
影响因子：
6.4
通讯作者：
Shapiro, SD
中科院分区：
文献类型：
--
作者：
Brody, SL;Yan, XH;Shapiro, SD
纤毛已被分类为感觉或运动类型的功能和结构特征的基础上，然而，调节不同纤毛类型的组装的重要因素还没有得到很好的理解。肝细胞核因子-3/叉头同源物4（HFH-4）是一种有翼螺旋/叉头转录因子，在发育后期至成年期的呼吸道、输卵管和室管膜的纤毛细胞中表达。有针对性地删除Hfh 4基因导致气道上皮细胞中纤毛发生缺陷和随机左右不对称，因此一半的小鼠具有原位倒置。在HFH-4基因敲除小鼠中，上皮细胞（包括气道中的上皮细胞）中不存在具有9 + 2微管超微结构的经典运动型纤毛。在其他器官，感觉纤毛与9 + 0微管模式，如嗅觉神经上皮细胞，存在。对缺失9 + 2纤毛的突变细胞的超微结构分析表明，纤毛发生缺陷是由于异常的中心粒迁移和/或顶端膜对接，这表明HFH-4的功能是指导基体定位或锚定。在妊娠7.0至7.5天的野生型胚胎的评估显示，HFH 4在具有单纤毛的胚胎结细胞中表达，这与该因子在早期确定左右轴的结中的功能一致。HFH-4突变体胚胎的节点的分析表明，在没有气道纤毛，节点纤毛存在。这些观察结果表明，与9 + 2型纤毛发生相比，在气道中存在独立的调节途径，并支持HFH-4在纤毛发生和左右轴形成中的中心作用。
Cilia have been classified as sensory or motile types on the basis of functional and structural characteristics; however, factors important for regulation of assembly of different cilia types are not well understood. Hepatocyte nuclear factor-3/forkhead homologue 4 (HFH-4) is a winged helix/forkhead transcription factor expressed in ciliated cells of the respiratory tract, oviduct, and ependyma in late development through adulthood. Targeted deletion of the Hfh4 gene resulted in defective ciliogenesis in airway epithelial cells and randomized left-right asymmetry so that half the mice had situs inversus. In HFH-4-null mice, classic motile type cilia with a 9 + 2 microtubule ultrastructure were absent in epithelial cells, including those in the airways. In other organs, sensory cilia with a 9 + 0 microtubule pattern, such as those on olfactory neuroepithelial cells, were present. Ultrastructural analysis of mutant cells with absent 9 + 2 cilia demonstrated that defective ciliogenesis was due to abnormal centriole migration and/or apical membrane docking, suggesting that HFH-4 functions to direct basal body positioning or anchoring. Evaluation of wild-type embryos at gestational days 7.0 to 7.5 revealed Hfh4 expression in embryonic node cells that have monocilium, consistent with a function for this factor at the node in early determination of left-right axis. Analysis of the node of HFH-4 mutant embryos revealed that, in contrast to absent airway cilia, node cilia were present. These observations indicate that there are independent regulatory pathways for node ciliogenesis compared with 9 + 2 type ciliogenesis in airways, and support a central role for HFH-4 in ciliogenesis and left-right axis formation.