ccm1 cell autonomously regulates endothelial cellular morphogenesis and vascular tubulogenesis in zebrafish
ccm1 cell autonomously regulates endothelial cellular morphogenesis and vascular tubulogenesis in zebrafish
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DOI：
10.1093/hmg/ddn142
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发表时间：
2008-08-15
影响因子：
3.5
通讯作者：
Schulte-Merker, Stefan
中科院分区：
文献类型：
--
作者：
Hogan, Benjamin M.;Bussmann, Jeroen;Schulte-Merker, Stefan
脑海绵状血管畸形(CCM)是一种常见的血管畸形，其特征是大脑中的薄壁畸形血管簇。可遗传的形式是由CCM1、CCM2和CCM3的突变引起的，但尽管这些因素在血管生物学中很重要，但对它们的分子和细胞功能的了解仍然难以捉摸。在这里，我们描述了斑马鱼CCM胚胎模型的特征。斑马鱼胚胎中ccm1的缺失会导致主要血管的严重和进行性扩张，尽管内皮细胞的命运和数量正常。Ccm1突变体的血管扩张伴随着内皮细胞的渐进性扩散和管壁变薄，尽管超微结构正常的细胞-细胞接触。斑马鱼CCM2突变体表现出类似的血管缺陷。最后，我们发现CCM1的功能是细胞自主的，这表明在发育和发病过程中，CCM蛋白调节的是内皮细胞的形态发生。
Cerebral cavernous malformations (CCMs) are a prevalent class of vascular anomalies characterized by thin-walled clusters of malformed blood vessels in the brain. Heritable forms are caused by mutations in CCM1, CCM2 and CCM3, but despite the importance of these factors in vascular biology, an understanding of their molecular and cellular functions remains elusive. Here we describe the characterization of a zebrafish embryonic model of CCM. Loss of ccm1 in zebrafish embryos leads to severe and progressive dilation of major vessels, despite normal endothelial cell fate and number. Vascular dilation in ccm1 mutants is accompanied by progressive spreading of endothelial cells and thinning of vessel walls despite ultrastructurally normal cell-cell contacts. Zebrafish ccm2 mutants display comparable vascular defects. Finally, we show that ccm1 function is cell autonomous, suggesting that it is endothelial cellular morphogenesis that is regulated by CCM proteins during development and pathogenesis.