Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome-associated Sos1 mutation

Peng Chieh Chen, Hiroko Wakimoto, David Conner, Toshiyuki Araki, Tao Yuan, Amy Roberts, Christine E. Seidman, Roderick Bronson, Benjamin G. Neel, Jonathan G. Seidman, Raju Kucherlapati

研究成果: Article

57 引文 斯高帕斯(Scopus)

摘要

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-of-function 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.

原文English
頁(從 - 到)4353-4365
頁數13
期刊Journal of Clinical Investigation
120
發行號12
DOIs
出版狀態Published - 2010 十二月 1

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Chen, P. C., Wakimoto, H., Conner, D., Araki, T., Yuan, T., Roberts, A., Seidman, C. E., Bronson, R., Neel, B. G., Seidman, J. G., & Kucherlapati, R. (2010). Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome-associated Sos1 mutation. Journal of Clinical Investigation, 120(12), 4353-4365. https://doi.org/10.1172/JCI43910