A null mutation of Hhex results in abnormal cardiac development, defective vasculogenesis and elevated vegfa levels
A null mutation of Hhex results in abnormal cardiac development, defective vasculogenesis and elevated vegfa levels
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DOI：
10.1242/dev.01393
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发表时间：
2004-10-01
期刊：
影响因子：
4.6
通讯作者：
Bogue, CW
中科院分区：
文献类型：
--
作者：
Hallaq, H;Pinter, E;Bogue, CW
同源异型盒基因Hhex最近被证明对正常的肝脏、甲状腺和前脑发育至关重要。Hhex（-/-）小鼠在妊娠中期（E14.5）死亡，其早期死亡的原因尚不清楚。由于Hhex在E7.0时在发育中的血岛中、在E9.0-9.5时在发育中的脉管系统和心脏的内皮中以及在E8.5-9.0时在腹侧前肠内胚层中表达，因此假定其在心脏和血管发育中起关键作用。我们首次发现Hhex的无效突变导致心脏和血管发育的显著异常，包括：（1）血管发生缺陷，（2）右心室发育不全，（3）过度丰富的内膜垫伴室间隔缺损、流出道异常和房室（AV）瓣膜发育不良，（4）致密心肌的异常发育。在没有Hhex的情况下，内皮细胞垫的急剧扩大是由于细胞凋亡减少和上皮-间充质转化（EMT）失调。有趣的是，Hhex（-/-）小鼠心脏中的血管内皮生长因子A（Vegfa）水平在E9.5和E11.5之间升高了三倍，并且用截短的可溶性Vegfa受体1（sFit-1，一种VEGF信号传导抑制剂）处理培养的Hhex（-/-）AV外植体，完全消除了在没有Hhex的情况下观察到的过度上皮-间充质转化。因此，腹侧前肠内胚层和/或内皮中的Hhex表达对于体内正常心血管发育是必需的，并且Hhex的一个功能是在发育期间抑制Vegfa水平。
The homeobox gene Hhex has recently been shown to be essential for normal liver, thyroid and forebrain development. Hhex(-/-) mice die by mid-gestation (E14.5) and the cause of their early demise remains unclear. Because Hhex is expressed in the developing blood islands at E7.0 in the endothelium of the developing vasculature and heart at E9.0-9.5, and in the ventral foregut endoderm at E8.5-9.0, it has been postulated to play a critical role in heart and vascular development. We show here, for the first time, that a null mutation of Hhex results in striking abnormalities of cardiac and vascular development which include: (1) defective vasculogenesis, (2) hypoplasia of the right ventricle, (3) overabundant endocardial cushions accompanied by ventricular septal defects, outflow tract abnormalities and atrio-ventricular (AV) valve dysplasia and (4) aberrant development of the compact myocardium. The dramatic enlargement of the endocardial cushions in the absence of Hhex is due to decreased apoptosis and dysregulated epithelial-mesenchymal transformation (EMT). Interestingly, vascular endothelial growth factor A (Vegfa) levels in the hearts of Hhex(-/-) mice were elevated as much as three-fold between E9.5 and E11.5, and treatment of cultured Hhex(-/-) AV explants with truncated soluble Vegfa receptor 1, sFIt-1, an inhibitor of Vegf signaling, completely abolished the excessive epithelial-mesenchymal transformation seen in the absence of Hhex. Therefore, Hhex expression in the ventral foregut endoderm and/or the endothelium is necessary for normal cardiovascular development in vivo, and one function of Hhex is to repress Vegfa levels during development.