Developmental SHP2 dysfunction underlies cardiac hypertrophy in Noonan syndrome with multiple lentigines.

Abstract

Hypertrophic cardiomyopathy is a common cause of mortality in congenital heart disease (CHD). Many gene abnormalities are associated with cardiac hypertrophy, but their function in cardiac development is not well understood. Loss-of-function mutations in PTPN11, which encodes the protein tyrosine phosphatase (PTP) SHP2, are implicated in CHD and cause Noonan syndrome with multiple lentigines (NSML), a condition that often presents with cardiac hypertrophic defects. Here, we found that NSML-associated hypertrophy stems from aberrant signaling mechanisms originating in developing endocardium. Trabeculation and valvular hyperplasia were diminished in hearts of embryonic mice expressing a human NSML-associated variant of SHP2, and these defects were recapitulated in mice expressing NSML-associated SHP2 specifically in endothelial, but not myocardial or neural crest, cells. In contrast, mice with myocardial- but not endothelial-specific NSML SHP2 expression developed ventricular septal defects, suggesting that NSML-associated mutations have both cell-autonomous and nonautonomous functions in cardiac development. However, only endothelial-specific expression of NSML-associated SHP2 induced adult-onset cardiac hypertrophy. Further, embryos expressing the NSML-associated SHP2 mutation exhibited aberrant AKT activity and decreased downstream forkhead box P1 (FOXP1)/FGF and NOTCH1/EPHB2 signaling, indicating that SHP2 is required for regulating reciprocal crosstalk between developing endocardium and myocardium. Together, our data provide functional and disease-based evidence that aberrant SHP2 signaling during cardiac development leads to CHD and adult-onset heart hypertrophy.

• Authors: Jessica Lauriol, Janel R Cabrera, Ashbeel Roy, Kimberly Keith, Sara M Hough, Federico Damilano, Bonnie Wang, Gabriel C Segarra, Meaghan E Flessa, Lauren E Miller, Saumya Das, Roderick Bronson, Kyu-Ho Lee, Maria I Kontaridis
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 126 Issue 8 Pg. 2989-3005 (08 01 2016) ISSN: 1558-8238 [Electronic] United States
• PMID: 27348588 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Protein Tyrosine Phosphatase, Non-Receptor Type 11
• Ptpn11 protein, mouse

Topics

• Animals
• Apoptosis
• Cardiomegaly (metabolism)
• Cell Lineage
• Disease Models, Animal
• Endocardium (metabolism)
• Female
• Gene Expression Regulation
• Heterozygote
• Homozygote
• Lentigo (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mutation
• Myocardium (metabolism)
• Myocytes, Cardiac (metabolism)
• Noonan Syndrome (metabolism)
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 (metabolism)
• Signal Transduction