Myocardial Mycn is essential for mouse ventricular wall morphogenesis.
Myocardial Mycn is essential for mouse ventricular wall morphogenesis.
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DOI：
10.1016/j.ydbio.2012.10.005
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发表时间：
2013-01-01
影响因子：
2.7
通讯作者：
Jiao K
中科院分区：
文献类型：
--
作者：
Harmelink C;Peng Y;DeBenedittis P;Chen H;Shou W;Jiao K
MYCN是一种高度保守的转录因子，在发育和疾病中具有多方面的作用。MYCN的突变与Feingold综合征有关，Feingold综合征是一种发育障碍，部分特征是先天性心脏缺陷。小鼠模型有助于阐明MYCN功能;然而，其在发育过程中的心脏特异性作用仍不清楚。我们采用Cre/loxp策略来揭示MYCN在发育中的小鼠心肌中的特异性活性。Mycn的心肌缺失导致薄心肌壁缺损，小梁形成显著减少。突变型心脏缺陷非常类似于由BMP 10和神经调节蛋白-1（NRG 1）信号通路（心肌壁发育的两种中心介质）中断引起的表型。我们进一步的研究表明，MYCN的表达受到BMP和NRG 1信号的调节。突变心脏的薄壁缺陷是由细胞增殖和细胞大小的减少引起的。MYCN通过调节细胞周期调节因子（包括CCND 1、CCND 2和ID 2）的表达促进心肌细胞增殖，并通过调节p70 S6 K的表达促进心肌细胞生长。此外，多种肌节蛋白的表达在Mycn心肌失活胚胎中改变，表明其对心肌细胞分化的重要作用。总之，Mycn作用于BMP和NRG 1心源性信号通路的下游，以促进正常的心肌壁形态发生。
MYCN is a highly conserved transcription factor with multifaceted roles in development and disease. Mutations in MYCN are associated with Feingold syndrome, a developmental disorder characterized in part by congenital heart defects. Mouse models have helped elucidate MYCN functions; however its cardiac-specific roles during development remain unclear. We employed a Cre/loxp strategy to uncover the specific activities of MYCN in the developing mouse myocardium. Myocardial deletion of Mycn resulted in a thin-myocardial wall defect with dramatically reduced trabeculation. The mutant heart defects strongly resemble the phenotype caused by disruption of BMP10 and Neuregulin-1 (NRG1) signaling pathways, two central mediators of myocardial wall development. Our further examination showed that expression of MYCN is regulated by both BMP and NRG1 signaling. The thin-wall defect in mutant hearts is caused by a reduction in both cell proliferation and cell size. MYCN promotes cardiomyocyte proliferation through regulating expression of cell cycle regulators (including CCND1, CCND2, and ID2) and promotes cardiomyocyte growth through regulating expression of p70S6K. In addition, expression of multiple sarcomere proteins is altered in Mycn myocardial-inactivation embryos, indicating its essential role for proper cardiomyocyte differentiation. In summary, Mycn acts downstream of BMP and NRG1 cardiogenic signaling pathways to promote normal myocardial wall morphogenesis.
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