Mediating ERK1/2 signaling rescues congenital heart defects in a mouse model of Noonan syndrome
Mediating ERK1/2 signaling rescues congenital heart defects in a mouse model of Noonan syndrome
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DOI：
10.1172/jci30756
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发表时间：
2007-08-01
影响因子：
15.9
通讯作者：
Robbins, Jeffrey
中科院分区：
文献类型：
--
作者：
Nakamura, Tomoki;Colbert, Melissa;Robbins, Jeffrey
努南综合征（NS）是一种常染色体显性遗传疾病，其特征是广泛的缺陷，最常见的包括比例矮小，颅面畸形和先天性心脏病（CHD）。NS是CHD最常见的非染色体病因，80%-90%的NS患者有心脏受累。蛋白酪氨酸磷酸酶Src同源区2，磷酸酶2（SHP 2）内的突变是约50%的NS伴心脏受累病例的原因。为了了解NS SHP 2功能获得性突变Q79 R的发育阶段和细胞类型特异性后果，我们产生了转基因小鼠，其中突变蛋白在妊娠期间或出生后在心肌细胞中表达。Q79 R SHP 2胚胎心脏显示心肌细胞周期改变，心室致密化不全和室间隔缺损，而在出生后的心肌细胞中，Q79 R SHP 2表达是完全良性的。Q79 R的胎儿表达导致ERK 1/2通路的特异性激活，并且将Q79 R转基因物培育到ERK 1/2无效背景中证实了该通路在介导突变体SHP 2的作用中的必要性和充分性。我们的数据建立了NS中Q79 R心脏表达的发育阶段特异性效应;表明随后的ERK 1/2激活的消融可防止心脏异常的发展;并表明ERK 1/2调节可能对开发CHD治疗策略具有重要意义。
Noonan syndrome (NS) is an autosomal dominant disorder characterized by a wide spectrum of defects, which most frequently include proportionate short stature, craniofacial anomalies, and congenital heart disease (CHD). NS is the most common nonchromosomal cause of CHD, and 80%-90% of NS patients have cardiac involvement. Mutations within the protein tyrosine phosphatase Src homology region 2, phosphatase 2 (SHP2) are responsible for approximately 50% of the cases of NS with cardiac involvement. To understand the developmental stage- and cell type-specific consequences of the NS SHP2 gain-of-function mutation, Q79R, we generated transgenic mice in which the mutated protein was expressed during gestation or following birth in cardiomyocytes. Q79R SHP2 embryonic hearts showed altered cardiomyocyte cell cycling, ventricular noncompaction, and ventricular septal defects, while, in the postnatal cardiomyocyte, Q79R SHP2 expression was completely benign. Fetal expression of Q79R led to the specific activation of the ERK1/2 pathway, and breeding of the Q79R transgenics into ERK1/2-null backgrounds confirmed the pathway's necessity and sufficiency in mediating mutant SHP2's effects. Our data establish the developmental stage-specific effects of Q79R cardiac expression in NS; show that ablation of subsequent ERK1/2 activation prevents the development of cardiac abnormalities; and suggest that ERK1/2 modulation could have important implications for developing therapeutic strategies in CHD.