Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome-associated Sos1 mutation
Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome-associated Sos1 mutation
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DOI：
10.1172/jci43910
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发表时间：
2010-12-01
影响因子：
15.9
通讯作者：
Kucherlapati, Raju
中科院分区：
文献类型：
--
作者：
Chen, Peng-Chieh;Wakimoto, Hiroko;Kucherlapati, Raju
努南综合征（NS）是一种常染色体显性遗传疾病，其特征是身材矮小，独特的面部特征和先天性心脏病。大约10%-15%的NS患者存在sons of sevenless 1（SOS 1）突变，该突变编码RAS和RAC鸟嘌呤核苷酸交换因子（GEF）。为了了解SOS 1在NS发病机制中的作用，我们产生了具有NS相关的Sos 1 E846 K获得性功能突变的小鼠。杂合和纯合突变小鼠均表现出许多NS相关表型，包括生长延迟、独特的面部畸形、血液学异常和心脏缺陷。我们发现Ras/MAPK途径以及Rac和Stat 3在突变心脏中被激活。这些数据提供了体内分子和细胞证据，表明Sos 1是Rac在生理条件下的GEF，并表明Rac和Stat 3激活可能有助于NS表型。此外，产前给予MEK抑制剂改善了纯合子突变小鼠的胚胎致死率、心脏缺陷和NS特征，表明该信号传导途径可能代表NS的有希望的治疗靶点。
Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, unique facial features, and congenital heart disease. About 10%-15% of individuals with NS have mutations in son of sevenless 1 (SOS1), which encodes a RAS and RAC guanine nucleotide exchange factor (GEF). To understand the role of SOS1 in the pathogenesis of NS, we generated mice with the NS-associated Sos1E846K gain-offunction mutation. Both heterozygous and homozygous mutant mice showed many NS-associated phenotypes, including growth delay, distinctive facial dysmorphia, hematologic abnormalities, and cardiac defects. We found that the Ras/MAPK pathway as well as Rac and Stat3 were activated in the mutant hearts. These data provide in vivo molecular and cellular evidence that Sos1 is a GEF for Rac under physiological conditions and suggest that Rac and Stat3 activation might contribute to NS phenotypes. Furthermore, prenatal administration of a MEK inhibitor ameliorated the embryonic lethality, cardiac defects, and NS features of the homozygous mutant mice, demonstrating that this signaling pathway might represent a promising therapeutic target for NS.