Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome–associated Sos1 mutation
Peng-Chieh Chen, … , Jonathan G. Seidman, Raju Kucherlapati
Peng-Chieh Chen, … , Jonathan G. Seidman, Raju Kucherlapati
Published November 1, 2010
Citation Information: J Clin Invest. 2010;120(12):4353-4365. https://doi.org/10.1172/JCI43910.
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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 4

Cardiac defects in Sos1+/EK mice.

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Cardiac defects in Sos1+/EK mice. (A) Representative H&E-stained...
(A) Representative H&E-stained transverse sections, showing AS (arrow) in Sos1+/EK hearts. Ao, aorta. Original magnification, ×10. (B) Representative Doppler image, with measurement of ascending aortic peak velocity of an 8-month-old Sos1+/EK mouse. (C) Representative M-mode (left parasternal short axis view; top) and 2D (left parasternal long and short axes; bottom) echocardiographic images obtained from 8-month-old mice. Green bars (bottom) indicate the thickness of interventricular septum. IVS, IVS thickness; LVId, left ventricular dimension at diastole; LVIs, left ventricular dimension at systole; LVPW, left ventricular posterior wall thickness. (D–F) Representative Masson trichrome staining showing fibrosis in the hearts of a 9-month-old Sos1+/EK mouse (right) but not in a WT littermate (left). (D) Original magnification, ×4. (E and F) Original magnification, ×10. (G) Immunofluorescence staining of collagen III (Col III) in the left ventricular wall. Original magnification, ×40. (H) TUNEL assay costained with the cardiomyocyte marker Troponin T, showing cardiomyocyte death in a Sos1+/EK heart; the right panel shows a higher magnification view. Arrows indicate TUNEL positive cells. Original magnification, ×40 and ×64. (I) Representative quantitative real-time PCR results, showing increased expression of cardiac hypertrophic markers in the Sos1+/EK hearts. Error bars indicate SD. **P < 0.01; ***P < 0.001.