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
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
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Research Article Genetics

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

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.

Authors

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

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Figure 5

Short stature and facial dysmorphia in Sos1EK mice.

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Short stature and facial dysmorphia in Sos1EK mice. (A) Representati...
(A) Representative appearance of 3-month-old littermates, showing reduced body length and size in Sos1 mutant mice. (B) Body weights of WT and mutant male mice with lines fit by linear regression. (P < 0.001 for Sos1+/EK versus WT and P < 0.05 for Sos1EK/EK versus WT.) (C) Facial defects in 3-month-old Sos1 mice. Arrowheads indicate blunt noses of mutant mice. (D) CT scans of 3-month-old mice. A sagittal projection (top row) and a coronal projection (bottom row) are shown. Numbers refer to the measurements shown in E. (E) Morphometric characteristics of the mice. Measurements were obtained on the CT sections at the same axial, coronal, and sagittal reference position in all mice (n = 3 for each genotype). Numbers are shown with SD. *P < 0.05, **P < 0.01, ***P < 0.001.