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 8

Prenatal treatment with the MEK inhibitor blocks development of NS features.

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Prenatal treatment with the MEK inhibitor blocks development of NS featu...
(A) H&E-stained sections of hearts from PD0325901-treated mice at P2. The asterisk indicates ASD. Top panel, original magnification, ×20. Bottom panel, original magnification, ×4. (B) Immunoblot showing effects of PD0325901 treatment on Erk1/2 and Stat3 activation. (C) H&E-stained section of a PD0325901-treated Sos1EK/EK mouse that died at P14. Note ASD (arrow), hypertrophic right ventricle wall (asterisk), and dilated epicardial vessels (arrowhead). (D) Representative sections of heart tissue of 3-month-old Sos1EK/EK mice with or without PD0325901 treatment. H&E-stained sections showing AS in the untreated mice (black arrowhead; row 1, original magnification, ×10). Masson Trichrome–stained sections showing fibrosis in untreated mice (rows 2–4). Note blue collagen staining (blue arrow) in left ventricular epicardium (row 2, original magnification, ×4), right atrial (RA) epicardium (row 3, original magnification, ×10), and right ventricular epicardium and myocardium (row 4, original magnification, ×10). Scale bar: 500 μm. (E) Body weight of treated and untreated male mice fit by linear regression. P < 0.01 for both PD0325901-treated Sos1+/EK mice versus PD0325901-treated WT mice and PD0325901-treated Sos1EK/EK mice versus PD0325901-treated WT mice. PD, PD0325901. (F) CT scans of treated and control mice (top row). A sagittal projection (top row) and a coronal projection (bottom row) are shown. Skull measurements are shown as in Figure 5E. *P < 0.05 when compared with WT.