Cardiac developmental defects and eccentric right ventricular hypertrophy in cardiomyocyte focal adhesion kinase (FAK) conditional knockout mice
Cardiac developmental defects and eccentric right ventricular hypertrophy in cardiomyocyte focal adhesion kinase (FAK) conditional knockout mice
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DOI：
10.1073/pnas.0802319105
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发表时间：
2008-05-06
影响因子：
11.1
通讯作者：
Guan, Jun-Lin
中科院分区：
文献类型：
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作者：
Peng, Xu;Wu, Xiaoyang;Guan, Jun-Lin
Focal adhesion kinase （FAK）是一种非受体酪氨酸激酶，在整合素介导的信号转导中起重要作用。为了探索FAK在心脏发育中的作用和机制，我们通过将FAK小鼠与myosin轻链2a (MLC2a) Cre小鼠杂交，使胚胎心肌细胞中的FAK失活，这些小鼠早在胚胎第9.5天就在心脏中表达了Cre。大多数由MLC2a-Cre （CFKO-2a）产生的条件FAK基因敲除小鼠在胚胎期死亡，心室壁薄，室间隔缺损。一小部分CFKO-2a小鼠存活至成年并伴有自发性偏心右心室肥厚。透射电镜分析显示CFKO-2a胚胎心肌细胞粗面内质网肿胀。我们发现，导致CFKO-2a小鼠脑室壁变薄的原因是细胞增殖减少，而不是细胞凋亡或分化增加。微阵列分析表明，心肌细胞增强因子2a （MEF2a）可受FAK调控，胚胎心脏中FAK的失活会损害MEF2a的表达。最后，我们发现Src在FAK调控MEF2a的信号转导中起重要作用，而不是PI3K。总之，这些结果确定了FAK在胚胎心脏发育中的作用和机制。
Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that plays an important role in integrin-mediated signal transduction. To explore the role and mechanisms of FAK in cardiac development, we inactivated FAK in embryonic cardiomyocytes by crossing the floxed FAK mice with myosin light chain-2a (MLC2a) Cre mice, which expressed Cre as early as embryonic day 9.5 in the heart. The majority of conditional FAK knockout mice generated from MLC2a-Cre (CFKO-2a) died in the embryonic stage with thin ventricular wall and ventricular septal defects. A small fraction of CFKO-2a mice survived to adulthood with spontaneous eccentric right ventricle hypertrophy. Transmission electron microscopy analysis displayed swelling in the rough endoplasmic reticulum in CFKO-2a embryonic cardiomyocytes. We found that decreased cell proliferation, but not increased cell apoptosis or differentiation, is the reason for the thin ventricular wall in CFKO-2a mice. Microarray analysis suggests that myocyte enhancer factor 2a (MEF2a) can be regulated by FAK and that inactivation of FAK in the embryonic heart compromised MEF2a expression. Last, we found that Src, but not PI3K, is important in mediating signal transduction for the regulation of MEF2a by FAK. Together, these results identified the role and mechanisms of FAK in embryonic cardiac development.