title: 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.forename: Jessica
authors.initials: J
authors.lastname: Lauriol
authors.forename: Janel R
authors.initials: JR
authors.lastname: Cabrera
authors.forename: Ashbeel
authors.initials: A
authors.lastname: Roy
authors.forename: Kimberly
authors.initials: K
authors.lastname: Keith
authors.forename: Sara M
authors.initials: SM
authors.lastname: Hough
authors.forename: Federico
authors.initials: F
authors.lastname: Damilano
authors.forename: Bonnie
authors.initials: B
authors.lastname: Wang
authors.forename: Gabriel C
authors.initials: GC
authors.lastname: Segarra
authors.forename: Meaghan E
authors.initials: ME
authors.lastname: Flessa
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Miller
authors.forename: Saumya
authors.initials: S
authors.lastname: Das
authors.forename: Roderick
authors.initials: R
authors.lastname: Bronson
authors.forename: Kyu-Ho
authors.initials: KH
authors.lastname: Lee
authors.forename: Maria I
authors.initials: MI
authors.lastname: Kontaridis
mesh_terms: D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000378:metabolism*; D019070:Cell Lineage; D004195:Disease Models, Animal; D004699:Endocardium / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006579:Heterozygote; D006720:Homozygote; D007911:Lentigo / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D009634:Noonan Syndrome / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse