Developmental SHP2 dysfunction underlies cardiac hypertrophy in Noonan syndrome with multiple lentigines
Jessica Lauriol, … , Kyu-Ho Lee, Maria I. Kontaridis
Jessica Lauriol, … , Kyu-Ho Lee, Maria I. Kontaridis
Published June 27, 2016
Citation Information: J Clin Invest. 2016;126(8):2989-3005. https://doi.org/10.1172/JCI80396.
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Research Article Cardiology

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

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Figure 1

The NSML phenotype is gene dosage dependent.

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The NSML phenotype is gene dosage dependent. (A) Primary MEFs were isola...
(A) Primary MEFs were isolated from control (Shp2+/+), NSML (Shp2Y279C/+ and Shp2Y279C/Y279C), NS (Shp2D61G/+), and Shp2 null (Shp2–/–) embryos, which were either left unstimulated or were stimulated with IGF-1 (10 nM) for 10 minutes, and SHP2 immune complex PTP assays were conducted using pNPP as substrate. Immunoblot control of immunoprecipitated SHP2 showing comparable recovery is shown. (B) Representative photographs of littermate mice at 12 weeks, showing relative lengths and craniofacial abnormalities of NSML mice. (C) Representative transverse cross-sections of whole hearts and H&E-, reticulin-, Masson-trichrome-, and collagen-stained sections. Scale bars: 200 μm (far left column); 50 μm (all other columns). (D) Heart–to–body weight (HW/BW) ratios. (E) Cardiomyocyte cross-sectional areas, n = 100–300 cells/genotype. (F) Percentage of fibrosis in 12-week-old Shp2+/+, Shp2Y279C/+, and Shp2Y279C/Y279C mice. n = 3–7 mice/group. Echocardiographic analyses of (G) LVPWth and (H) LVDd in 6-, 9-, and 12-week-old Shp2+/+, Shp2Y279C/+, and Shp2Y279C/Y279C mice. n = 3–7 mice/group. Data represent mean ± SEM. *P < 0.05; **P < 0.01. P values were derived from 1-way ANOVA with Bonferroni’s post-test when ANOVA was significant.