Disruption of planar cell polarity signaling results in congenital heart defects and cardiomyopathy attributable to early cardiomyocyte disorganization
Disruption of planar cell polarity signaling results in congenital heart defects and cardiomyopathy attributable to early cardiomyocyte disorganization
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DOI：
10.1161/circresaha.106.142406
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发表时间：
2007-07-20
影响因子：
20.1
通讯作者：
Henderson, Deborah J.
中科院分区：
文献类型：
--
作者：
Phillips, Helen M.;Rhee, Hong Jun;Henderson, Deborah J.
果蝇scribble基因调节顶端-基底极性，并参与细胞结构和细胞生长控制。哺乳动物Scrib（circletail; Crc突变体）的突变也会导致异常，提示在平面细胞极性调节中的作用。我们表明，Crc突变发展心脏畸形和心肌病归因于心肌细胞组织内的早期心管异常。N-钙粘蛋白从心肌细胞膜上丢失，细胞间粘附被破坏。这导致心脏成环异常以及小梁和致密心肌的形成，最终导致心脏错位缺陷和心室致密化不全。因此，这些晚期异常是由心脏发育最早阶段发生的缺陷引起的。Vangl 2在Crc/Crc心肌细胞中的错误定位表明Scrib在该组织中的平面细胞极性途径中起作用。此外，Scrib和Vangl 2突变的双杂合性可导致心脏缺陷，类似于每个基因的纯合突变体中发现的心脏缺陷，但没有其他主要缺陷。我们认为，平面细胞极性通路中不同基因突变的杂合性可能是人类先天性心脏病和心肌病的重要机制。
The Drosophila scribble gene regulates apical-basal polarity and is implicated in control of cellular architecture and cell growth control. Mutations in mammalian Scrib ( circletail; Crc mutant) also result in abnormalities suggestive of roles in planar cell polarity regulation. We show that Crc mutants develop heart malformations and cardiomyopathy attributable to abnormalities in cardiomyocyte organization within the early heart tube. N-Cadherin is lost from the cardiomyocyte cell membrane and cell-cell adhesion is disrupted. This results in abnormalities in heart looping and formation of both the trabeculae and compact myocardium, which ultimately results in cardiac misalignment defects and ventricular noncompaction. Thus, these late abnormalities arise from defects occurring at the earliest stages of heart development. Mislocalization of Vangl2 in Crc/Crc cardiomyocytes suggests Scrib is acting in the planar cell polarity pathway in this tissue. Moreover, double heterozygosity for mutations in both Scrib and Vangl2 can cause cardiac defects similar to those found in homozygous mutants for each gene but without other major defects. We propose that heterozygosity for mutations in different genes in the planar cell polarity pathway may be an important mechanism for congenital heart defects and cardiomyopathy in humans.