Cardiac Neural Crest Expression of Hand2 Regulates Outflow and Second Heart Field Development
Cardiac Neural Crest Expression of Hand2 Regulates Outflow and Second Heart Field Development
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DOI：
10.1161/circresaha.108.180083
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发表时间：
2008-12-05
影响因子：
20.1
通讯作者：
Cserjesi, Peter
中科院分区：
文献类型：
--
作者：
Morikawa, Yuka;Cserjesi, Peter
心脏神经嵴（cNC）谱系通过直接促进心脏结构和调节其他心脏谱系的发育在心脏发育中起关键作用。基础螺旋-环-螺旋因子Hand 2调节心血管结构和NC衍生组织的发育，包括那些有助于面部和外周神经系统的组织。虽然Hand 2在cNC中表达，但由于当Hand 2在NC谱系中缺失时的早期胚胎致死性，其作用尚未被研究。我们发现，致死性是由于去甲肾上腺素合成的损失，可以通过激活肾上腺素能受体来克服。在挽救的胚胎中，NC谱系中Hand 2的缺失导致流出道和主动脉弓动脉的错位。缺陷包括肺动脉瓣狭窄、主动脉中断、食管后右锁骨下动脉和室间隔缺损，类似于NC缺陷引起的先天性心脏缺陷。Hand 2部分通过调节从cNC到其他心脏谱系的信号传导而不是通过调节cNC的迁移或存活来发挥作用。NC中Hand 2的缺失还揭示了cNC在调节第二心脏场衍生心肌的增殖和分化中的新作用，该作用持续到发育后期。这些结果表明，cNC功能作为心脏发育的主要信号中心和Hand 2起着关键作用，在调节细胞自主和非自主功能的cNC。(Circ Res. 2008;103：1422-1429）。
The cardiac neural crest (cNC) lineage plays key roles in heart development by directly contributing to heart structures and regulating development of other heart lineages. The basic helix-loop-helix factor Hand2 regulates development of cardiovascular structures and NC-derived tissues including those that contribute to face and peripheral nervous system. Although Hand2 is expressed in cNC, its role has not been examined because of an early embryonic lethality when Hand2 is deleted in the NC lineage. We find that the lethality is attributable to loss of norepinephrine synthesis that can be overcome by activating adrenergic receptors. In rescued embryos, loss of Hand2 in the NC lineage leads to the misalignment of the outflow tract and aortic arch arteries. Defects include pulmonary stenosis, interrupted aortic artery, retroesophageal right subclavian artery, and ventricular septum defect, which resemble congenital heart defects attributed to defects in the NC. Hand2 functions in part by regulating signaling from the cNC to other cardiac lineages but not by regulating migration or survival of the cNC. Loss of Hand2 in NC also uncovered a novel role for the cNC in regulating proliferation and differentiation of the second heart field-derived myocardium that persists late into development. These results show that the cNC functions as a major signaling center for heart development and Hand2 plays a pivotal role in regulating both cell-autonomous and-nonautonomous functions of the cNC. (Circ Res. 2008;103:1422-1429.)