Activation of multiple signaling pathways  causes developmental defects in mice with a Noonan syndrome–associated Sos1 mutation.
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 pheno-types, 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.
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
Peng-Chieh
PC
Chen
Hiroko
H
Wakimoto
David
D
Conner
Toshiyuki
T
Araki
Tao
T
Yuan
Amy
A
Roberts
Christine  E
C
Seidman
Roderick
R
Bronson
Benjamin  G
B
Neel
Jonathan G
JG
Seidman
Raju
R
Kucherlapati
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006321:Heart / Q000196:embryology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009634:Noonan Syndrome / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011247:Pregnancy; D020837:SOS1 Protein / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D020837:SOS1 Protein; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D020744:rac GTP-Binding Proteins