Loss of microRNAs in neural crest leads to cardiovascular syndromes resembling human congenital heart defects.
Loss of microRNAs in neural crest leads to cardiovascular syndromes resembling human congenital heart defects.
复制标题
神经嵴中 microRNA 的丢失会导致类似于人类先天性心脏缺陷的心血管综合征。
DOI：
10.1161/atvbaha.110.213306
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发表时间：
2010-12
影响因子：
8.7
通讯作者：
Wang, Da-Zhi
中科院分区：
文献类型：
--
作者：
Huang, Zhan-Peng;Chen, Jian-Fu;Regan, Jenna N.;Maguire, Colin T.;Tang, Ru-Hang;Dong, Xiu Rong;Majesky, Mark W.;Wang, Da-Zhi
先天性心脏病（CHD）是人类最常见的出生缺陷。尽管这些综合征的遗传原因与各自的候选基因有关，但其潜在的分子机制仍在很大程度上未知。神经嵴细胞（NCC）迁移到咽弓和囊的衍生物的干扰可以解释许多发育缺陷。目的探讨miRNA在NCC及心血管系统中的作用。我们从神经嵴细胞（NCC）谱系中删除了Dicer，并表明Dicer条件突变体在多种颅面和心血管结构中表现出严重的缺陷，其中许多在人类NCCS患者中观察到。我们发现，颅NCC需要Dicer才能生存，Dicer的缺失导致大量细胞死亡和NCC衍生的颅面结构的完全丧失。相反，Dicer和miRNAs对于心脏NCC的存活不是必需的。然而，在Dicer基因敲除小鼠中，这些细胞的迁移和图案化受损，导致一系列心血管异常，包括B型主动脉弓中断（IAA-B）、右心室双出口（DORV）和室间隔缺损（VSD）。我们发现，Dicer功能丧失至少部分是由miR-21和miR-181 a介导的，这反过来又抑制了Erk 1/2信号传导抑制剂Sprouty 2的蛋白水平。我们的研究结果揭示了Dicer和miRNA在颅面和心血管发育中的神经嵴细胞存活、迁移和图案化中的核心作用，当突变时，导致先天性神经颅面心脏缺陷。
Congenital heart defects (CHD) represent the most common human birth defects. Even though the genetic cause for these syndromes has been linked to respective candidate genes, the underlying molecular mechanisms are still largely unknown. Disturbance of neural crest cell (NCC) migration into the derivatives of the pharyngeal arches and pouches can account for many of the developmental defects. To investigate the function of miRNA in NCCs and cardiovascular system. we deleted Dicer from neural crest cell (NCC) lineage and showed that Dicer conditional mutants exhibit severe defects in multiple craniofacial and cardiovascular structures, many of them are observed in human NCCS patients. We found that cranial NCCs require Dicer for their survival and deletion of Dicer led to massive cell death and complete loss of NCC-derived craniofacial structures. In contrast, Dicer and miRNAs were not essential for the survival of cardiac NCCs. However, the migration and patterning of these cells were impaired in Dicer knockout mice, resulting in a spectrum of cardiovascular abnormalities, including Type B Interrupted Aortic Arch (IAA-B), Double Outlet Right Ventricle (DORV) and Ventricular Septal Defect (VSD). We show that Dicer loss-of-function was, at least in part, mediated by miR-21 and miR-181a, which in turn, repressed the protein level of Sprouty 2, an inhibitor of Erk1/2 signaling. Our results uncovered a central role for Dicer and miRNAs in neural crest cells survival, migration and patterning in craniofacial and cardiovascular development which, when mutated, lead to congenital neuro-craniofacial-cardiac defects.