WDR1-regulated actin dynamics is required for outflow tract and right ventricle development
WDR1-regulated actin dynamics is required for outflow tract and right ventricle development
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WDR1 调节的肌动蛋白动力学是流出道和右心室发育所必需的
DOI：
10.1016/j.ydbio.2018.04.004
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发表时间：
2018-06-15
影响因子：
2.7
通讯作者：
Yuan, Baiyin
中科院分区：
文献类型：
--
作者：
Hu, Jisheng;Shi, Yingchao;Yuan, Baiyin
流出道（OFT）异常占出生时检测到的人类先天性心脏病的约30%。第二心野（SHF）祖细胞有助于OFT和右心室（RV）的发育，但这一过程在很大程度上仍不清楚。WDR 1（WD-重复结构域1）是肌动蛋白解聚因子（ADF）/cofilin的主要辅因子，其主动分解ADF/cofilin结合的肌动蛋白丝。它在胚胎心脏发育中的功能尚不清楚。用Wdr 1基因敲除小鼠和Nkx2.5-Cre基因敲除小鼠的胚胎心脏Wdr 1基因（Wdr 1（F/F）;Nkx2.5-Cre），发现这些小鼠出现胚胎死亡、OFT和RV发育不良。为了研究WDR 1在OFT和RV发育中的作用，我们产生了SHF祖细胞特异性Wdr 1缺失小鼠（shfKO）。shfKO小鼠在胚胎第11.5天（E11.5）开始死亡，并且在E10.5时显示近端OFT和RV的尺寸减小。在shfKO胚胎中，部署到OFT的SHF细胞的数量和细胞增殖以及细胞数量都没有改变，而心肌细胞的细胞组织和肌原纤维组装严重破坏。在shfKO和Wdr 1（F/F）;Nkx2.5-Cre胚胎的近端OFT和RV中，心肌细胞从外部致密心肌层解离，松散且无序地排列成多层心肌。我们的研究结果表明，WDR 1是不可或缺的正常OFT和RV的发展，并建议WDR 1介导的肌动蛋白动力学功能，在控制OFT和RV的大小，这可能是通过调节心肌细胞的空间排列。
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(F/F);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(F/F);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.