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. During studies of genetic interaction between Egfr, encoding the epidermal growth factor receptor, and Ptpn11, encoding the protein-tyrosine-phosphatase Shp2, we discovered that Egfr is required for semilunar, but not atrioventricular, valve development. Although unnoticed in earlier studies, mice homozygous for the hypomorphic Egfr allele waved-2 (Egfrwa2/wa2) exhibit semilunar valve enlargement resulting from over-abundant mesenchymal cells. Egfr-/- mice (CD1 background) have similar defects. The penetrance and severity of the defects in Egfrwa2/wa2 mice are enhanced by heterozygosity for a targeted mutation of exon 2 of Ptpn11 (ref. 3). Compound (Egfrwa2/wa2:Ptpn11+/-) mutant mice also show premature lethality. Electrocardiography, echocardiography and haemodynamic analyses showed that affected mice develop aortic stenosis and regurgitation. Our results identify the Egfr and Shp2 as components of a growth-factor signalling pathway required specifically for semilunar valvulogenesis, support the hypothesis that Shp2 is required for Egfr signalling in vivo, and provide an animal model for aortic valve disease.
Chen
B
B
Cancer Biology Program, Hematology/Oncology Division, Boston, Massachusetts, USA.
Bronson
R T
RT
Klaman
L D
LD
Hampton
T G
TG
Wang
J F
JF
Green
P J
PJ
Magnuson
T
T
Douglas
P S
PS
Morgan
J P
JP
Neel
B G
BG
D000015:Abnormalities, Multiple / Q000235:genetics; D000818:Animals; D001021:Aortic Valve / Q000002:abnormalities* / Q000196:embryology / Q000473:pathology; D001022:Aortic Valve Insufficiency / Q000235:genetics; D001024:Aortic Valve Stenosis / Q000235:genetics; D004843:Epistasis, Genetic; D066246:ErbB Receptors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005838:Genotype; D006329:Heart Conduction System / Q000503:physiopathology; D006965:Hyperplasia; D047908:Intracellular Signaling Peptides and Proteins; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology*; D011664:Pulmonary Valve / Q000002:abnormalities* / Q000196:embryology / Q000473:pathology; D017384:Sequence Deletion; D018487:Ventricular Dysfunction, Left / Q000235:genetics
D047908:Intracellular Signaling Peptides and Proteins; D066246:ErbB Receptors; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse