β-Catenin regulates endocardial cushion growth by suppressing p21.
β-Catenin regulates endocardial cushion growth by suppressing p21.
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DOI：
10.26508/lsa.202302163
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发表时间：
2023-09
影响因子：
4.4
通讯作者：
中科院分区：
文献类型：
--
作者：
这项工作表明，β-连环蛋白介导的 p21 抑制对于心内膜垫的形成至关重要，表明 β-连环蛋白在先天性心脏缺陷的病因学中具有潜在作用。心内膜垫的形成对于心脏瓣膜发育和心室分离至关重要。心内膜垫形成异常通常会导致先天性心脏缺陷。 β-连环蛋白已知对于心内膜垫的形成至关重要；然而，潜在的细胞和分子机制仍未完全了解。在这里，我们发现，小鼠体内β-连环蛋白的内皮特异性缺失导致由于细胞增殖减少和细胞迁移受损而形成发育不全的心内膜垫。通过使用选择性破坏β-catenin转录功能的β-cateninDM等位基因，我们进一步揭示β-catenin分别通过其转录和非转录功能调节细胞增殖和迁移。在分子水平上，β-连环蛋白的缺失导致体内心内膜和间充质细胞中细胞周期抑制剂 p21 的表达增加。 HUVEC 和猪主动脉瓣间质细胞的体外拯救实验证实，β-连环蛋白通过抑制 p21 促进细胞增殖。此外，一项精明的负面观察是，β-连环蛋白对于心内膜到间质命运的改变是可有可无的。总而言之，我们的研究结果表明，β-连环蛋白对于细胞增殖和迁移至关重要，但对于心内膜细胞在心内膜垫形成过程中获得间充质命运来说是可有可无的。从机制上讲，β-连环蛋白通过抑制 p21 促进细胞增殖。这些发现揭示了 β-连环蛋白在先天性心脏缺陷病因学中的潜在作用。
This work demonstrates that β-catenin–mediated suppression of p21 is essential for endocardial cushion formation, suggesting a potential role of β-catenin in the etiology of congenital heart defects. Endocardial cushion formation is essential for heart valve development and heart chamber separation. Abnormal endocardial cushion formation often causes congenital heart defects. β-Catenin is known to be essential for endocardial cushion formation; however, the underlying cellular and molecular mechanisms remain incompletely understood. Here, we show that endothelial-specific deletion of β-catenin in mice resulted in formation of hypoplastic endocardial cushions due to reduced cell proliferation and impaired cell migration. By using a β-cateninDM allele in which the transcriptional function of β-catenin is selectively disrupted, we further reveal that β-catenin regulated cell proliferation and migration through its transcriptional and non-transcriptional function, respectively. At the molecular level, loss of β-catenin resulted in increased expression of cell cycle inhibitor p21 in cushion endocardial and mesenchymal cells in vivo. In vitro rescue experiments with HUVECs and pig aortic valve interstitial cells confirmed that β-catenin promoted cell proliferation by suppressing p21. In addition, one savvy negative observation is that β-catenin was dispensable for endocardial-to-mesenchymal fate change. Taken together, our findings demonstrate that β-catenin is essential for cell proliferation and migration but dispensable for endocardial cells to gain mesenchymal fate during endocardial cushion formation. Mechanistically, β-catenin promotes cell proliferation by suppressing p21. These findings inform the potential role of β-catenin in the etiology of congenital heart defects.
影响因子：
3.8
作者：
Odenwald MA;Prosperi JR;Goss KH
通讯作者：
Goss KH