Hu Jisheng, Shi Yingchao, Xia Meng, Liu Zhongying, Zhang Ruirui, Luo Hongmei, Zhang Tongcun, Yang Zhongzhou, Yuan Baiyin
Biomedical Research Institute, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei Province 430065, China.
MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing 210061, China.
Dev Biol. 2018 Jun 15;438(2):124-137. doi: 10.1016/j.ydbio.2018.04.004. Epub 2018 Apr 11.
Outflow tract (OFT) anomalies account for about 30% of human congenital heart defects detected at birth. The second heart field (SHF) progenitors contribute to OFT and right ventricle (RV) development, but the process largely remains unknown. WDR1 (WD-repeat domain 1) is a major co-factor of actin depolymerizing factor (ADF)/cofilin that actively disassembles ADF/cofilin-bound actin filaments. Its function in embryonic heart development has been unknown. Using Wdr1 floxed mice and Nkx2.5-Cre, we deleted Wdr1 in embryonic heart (Wdr1;Nkx2.5-Cre) and found that these mice exhibited embryonic lethality, and hypoplasia of OFT and RV. To investigate the role of WDR1 in OFT and RV development, we generated SHF progenitors-specific Wdr1 deletion mice (shfKO). shfKO mice began to die at embryonic day 11.5 (E11.5), and displayed decreased size of the proximal OFT and RV at E10.5. In shfKO embryos, neither the number of SHF cells deployment to OFT nor cell proliferation and the cell number were changed, whereas the cellular organization and myofibrillar assembly of cardiomyocytes were severely disrupted. In the proximal OFT and RV of both shfKO and Wdr1;Nkx2.5-Cre embryos, cardiomyocytes were dissociated from the outer compact myocardial layer and loosely and disorderly arranged into multilayered myocardium. Our results demonstrate that WDR1 is indispensable for normal OFT and RV development, and suggest that WDR1-mediated actin dynamics functions in controlling the size of OFT and RV, which might through regulating the spatial arrangement of cardiomyocytes.
流出道（OFT）异常占出生时检测到的人类先天性心脏缺陷的约30%。第二心脏场（SHF）祖细胞参与OFT和右心室（RV）的发育，但该过程在很大程度上仍不清楚。WDR1（WD重复结构域1）是肌动蛋白解聚因子（ADF）/丝切蛋白的主要辅助因子，可积极拆解与ADF/丝切蛋白结合的肌动蛋白丝。其在胚胎心脏发育中的功能尚不清楚。利用Wdr1条件性敲除小鼠和Nkx2.5-Cre，我们在胚胎心脏中删除了Wdr1（Wdr1;Nkx2.5-Cre），发现这些小鼠表现出胚胎致死性，以及OFT和RV发育不全。为了研究WDR1在OFT和RV发育中的作用，我们构建了SHF祖细胞特异性Wdr1缺失小鼠（shfKO）。shfKO小鼠在胚胎第11.5天（E11.5）开始死亡，并在E10.5时显示近端OFT和RV尺寸减小。在shfKO胚胎中，SHF细胞向OFT的部署数量、细胞增殖和细胞数量均未改变，而心肌细胞的细胞组织和肌原纤维组装受到严重破坏。在shfKO和Wdr1;Nkx2.5-Cre胚胎的近端OFT和RV中，心肌细胞从外层致密心肌层解离，松散且无序地排列成多层心肌。我们的结果表明，WDR1对于正常的OFT和RV发育是不可或缺的，并表明WDR1介导的肌动蛋白动力学在控制OFT和RV的大小中起作用，这可能是通过调节心肌细胞的空间排列来实现的。
