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

Research output: Contribution to journalArticlepeer-review

62 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4353-4365
Number of pages13
JournalJournal of Clinical Investigation
Volume120
Issue number12
DOIs
Publication statusPublished - 2010 Dec 1

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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