Mice mutant for Egfr and Shp2 have defective cardiac semilunar valvulogenesis
Mice mutant for Egfr and Shp2 have defective cardiac semilunar valvulogenesis
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DOI：
10.1038/73528
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发表时间：
2000-03-01
期刊：
影响因子：
30.8
通讯作者：
Neel, BG
中科院分区：
文献类型：
--
作者：
Chen, BB;Bronson, RT;Neel, BG
房室瓣和半月瓣畸形是常见的出生缺陷，但如何指导心脏瓣膜的发生仍不清楚。在编码表皮生长因子受体的Egfr和编码蛋白酪氨酸磷酸酶Shp 2的Ptpn 11之间的遗传相互作用的研究中，我们发现Egfr是半月瓣而不是房室瓣发育所需的。尽管在早期研究中未被注意到（1，2），2，但亚型Egfr等位基因waved-2（Egfr（wa 2/wa 2））纯合子小鼠表现出过度丰富的间充质细胞导致的半月瓣扩大。Egfr（-/-）小鼠（CD 1背景）具有类似的缺陷。Ptpn 11外显子2的靶向突变的杂合性增强了Egfr（wa 2/wa 2）小鼠缺陷的外显率和严重程度（参考文献3）。化合物（Egfr（wa 2/wa 2）：Ptpn 11（+/-））突变小鼠也显示过早致死。心电图、超声心动图和血液动力学分析表明，受影响的小鼠会出现主动脉瓣狭窄和反流。我们的研究结果确定了Egfr和Shp 2作为半月瓣形成所需的生长因子信号传导途径的组成部分，支持Shp 2是体内Egfr信号传导所需的假设，并提供了主动脉瓣疾病的动物模型。
Atrioventricular and semilunar valve abnormalities are common birth defects, but how cardiac valvulogenesis is directed remains largely unknown. During studies of genetic interaction between Egfr, encoding the epidermal growth factor receptor, and Ptpn11, encoding the protein-tyrosine-phosphatase Shp2, we discovered that Egfr is required for semilunar, but not atrioventricular, valve development. Although unnoticed in earlier studies(1,2), 2, mice homozygous for the hypomorphic Egfr allele waved-2 (Egfr(wa2/wa2)) exhibit semilunar valve enlargement resulting from over-abundant mesenchymal cells. Egfr(-/-) mice (CD1 background) have similar defects. The penetrance and severity of the defects in Egfr(wa2/wa2) mice are enhanced by heterozygosity for a targeted mutation of exon 2 of Ptpn11 (ref. 3). Compound (Egfr(wa2/wa2):Ptpn11(+/-)) mutant mice also show premature lethality. Electrocardiography, echocardiography and haemodynamic analyses showed that affected mice develop aortic stenosis and regurgitation. Our results identify the Egfr and Shp2 as components of a growth-factor signalling pathway required specifically for semilunar valvulogenesis, support the hypothesis that Shp2 is required for Egfr signalling in vivo, and provide an animal model for aortic valve disease.