NDLI: Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome

Content Provider	PubMed Central
Author	Chen, Peng-chieh Wakimoto, Hiroko Conner, David Araki, Toshiyuki Yuan, Tao Roberts, Amy Seidman, Christine E. Bronson, Roderick Neel, Benjamin G. Seidman, Jonathan G. Raju, Kucherlapati
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.
Related Links	http://dx.doi.org/10.1172/jci43910
Ending Page	4365
Page Count	13
Starting Page	4353
File Format	PDF
ISSN	00219738
e-ISSN	15588238
Journal	The Journal of Clinical Investigation
Issue Number	12
Volume Number	120
Language	English
Publisher	American Society for Clinical Investigation
Publisher Date	2010-12-01
Access Restriction	Open
Rights Holder	American Society for Clinical Investigation
Subject Keyword	Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Medicine

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