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Mice mutant for Egfr and Shp2 have defective cardiac semilunar valvulogenesis
B Chen1, R T Bronson, L D Klaman
1Cancer Biology Program, Hematology/Oncology Division, Boston, Massachusetts, USA.
Abstract:
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.
Insights
Epidermal growth factor receptor (EGFR) and Shp2 phosphatase are crucial for semilunar valve development in mice. Genetic interactions reveal their role in preventing aortic valve disease.
Area of Science:
- Cardiovascular biology
- Developmental biology
- Genetics
Background:
- Congenital heart defects involving atrioventricular and semilunar valves are common but poorly understood.
- The molecular mechanisms directing cardiac valvulogenesis remain largely unknown.
Purpose of the Study:
- To investigate the roles of Epidermal Growth Factor Receptor (EGFR) and Protein-Tyrosine Phosphatase Non-Receptor Type 11 (PTPN11/Shp2) in cardiac valve development.
- To elucidate the genetic interaction between EGFR and Shp2 in vivo.
- To establish an animal model for semilunar valve abnormalities.
Main Methods:
- Generation and analysis of mice with mutations in Egfr (hypomorphic allele waved-2 and null) and Ptpn11.
- Genetic interaction studies combining Egfr and Ptpn11 mutations.
- Phenotypic analysis including echocardiography, electrocardiography, and haemodynamic assessment.
Main Results:
- Egfr is essential for semilunar valve development but not atrioventricular valve development.
- Mice with Egfr mutations exhibit semilunar valve enlargement due to excess mesenchymal cells.
- Combined mutations in Egfr and Ptpn11 enhance defects and cause premature lethality.
- Mutant mice develop aortic stenosis and regurgitation.
Conclusions:
- EGFR and Shp2 function in a growth factor signaling pathway specifically required for semilunar valvulogenesis.
- Shp2 is necessary for EGFR signaling in vivo.
- These findings provide a novel animal model for studying aortic valve disease and its genetic underpinnings.