Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis.
Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis.
复制标题
DOI：
10.7554/elife.28939
复制
发表时间：
2018-02-01
期刊：
影响因子：
7.7
通讯作者：
Abdelilah-Seyfried S
中科院分区：
文献类型：
--
作者：
Donat S;Lourenço M;Paolini A;Otten C;Renz M;Abdelilah-Seyfried S
内皮细胞通过其机械敏感性的适应来响应不同水平的流体剪应力。目前，我们对它如何有助于心血管系统的雕刻缺乏很好的了解。脑海绵畸形(CCM)是一种遗传性血管疾病，当第二次体细胞突变导致CCM1/KRIT1、CCM2或CCM3蛋白丢失时发生。在这里，我们证明斑马鱼Krit1调节心脏瓣膜的形成。编码Krit1结合伴侣的heg1的表达受血流的正向调节。反过来，Heg1稳定了Krit1蛋白的水平，Heg1和Krit1都抑制了主要的机械敏感基因KLF2a的表达水平。相反，Krit1的缺失会导致KLF2a和notch1b在整个心内膜中的表达增加，并阻止心脏瓣膜叶的形成。因此，血流依赖的诱导和Krit1蛋白介导的对kLf2a和notch1b的抑制的正确平衡最终塑造了心脏瓣膜叶的形态。
Endothelial cells respond to different levels of fluid shear stress through adaptations of their mechanosensitivity. Currently, we lack a good understanding of how this contributes to sculpting of the cardiovascular system. Cerebral cavernous malformation (CCM) is an inherited vascular disease that occurs when a second somatic mutation causes a loss of CCM1/KRIT1, CCM2, or CCM3 proteins. Here, we demonstrate that zebrafish Krit1 regulates the formation of cardiac valves. Expression of heg1, which encodes a binding partner of Krit1, is positively regulated by blood-flow. In turn, Heg1 stabilizes levels of Krit1 protein, and both Heg1 and Krit1 dampen expression levels of klf2a, a major mechanosensitive gene. Conversely, loss of Krit1 results in increased expression of klf2a and notch1b throughout the endocardium and prevents cardiac valve leaflet formation. Hence, the correct balance of blood-flow-dependent induction and Krit1 protein-mediated repression of klf2a and notch1b ultimately shapes cardiac valve leaflet morphology.