Mice mutant for Egfr and Shp2 have defective cardiac semilunar valvulogenesis

Atrioventricular and semilunar valve abnormalities are common birth defects , but how cardiac valvulogenesis is directed remains largely unknown. Durin g studies of genetic interaction between Egfr, encoding the epidermal growt h factor receptor, and Ptpn11, encoding the protein-tyrosine-phosphatase Sh p2, we discovered that Egfr is required for semilunar, but not atrioventric ular, valve development. Although unnoticed in earlier studies(1,2), 2, mic e homozygous for the hypomorphic Egfr allele waved-2 (Egfr(wa2/wa2)) exhibi t semilunar valve enlargement resulting from over-abundant mesenchymal cell s. Egfr(-/-) mice (CD1 background) have similar defects. The penetrance and severity of the defects in Egfr(wa2/wa2) mice are enhanced by heterozygosi ty for a targeted mutation of exon 2 of Ptpn11 (ref. 3). Compound (Egfr(wa2 /wa2):Ptpn11(+/-)) mutant mice also show premature lethality. Electrocardio graphy, echocardiography and haemodynamic analyses showed that affected mic e develop aortic stenosis and regurgitation. Our results identify the Egfr and Shp2 as components of a growth-factor signalling pathway required speci fically for semilunar valvulogenesis, support the hypothesis that Shp2 is r equired for Egfr signalling in vivo, and provide an animal model for aortic valve disease.