Mediating ERK 1/2 signaling rescues congenital heart defects in a mouse model of Noonan syndrome

J Clin Invest. 2007 Aug;117(8):2123-32. doi: 10.1172/JCI30756.

Abstract

Noonan syndrome (NS) is an autosomal dominant disorder characterized by a wide spectrum of defects, which most frequently include proportionate short stature, craniofacial anomalies, and congenital heart disease (CHD). NS is the most common nonchromosomal cause of CHD, and 80%-90% of NS patients have cardiac involvement. Mutations within the protein tyrosine phosphatase Src homology region 2, phosphatase 2 (SHP2) are responsible for approximately 50% of the cases of NS with cardiac involvement. To understand the developmental stage- and cell type-specific consequences of the NS SHP2 gain-of-function mutation, Q79R, we generated transgenic mice in which the mutated protein was expressed during gestation or following birth in cardiomyocytes. Q79R SHP2 embryonic hearts showed altered cardiomyocyte cell cycling, ventricular noncompaction, and ventricular septal defects, while, in the postnatal cardiomyocyte, Q79R SHP2 expression was completely benign. Fetal expression of Q79R led to the specific activation of the ERK1/2 pathway, and breeding of the Q79R transgenics into ERK1/2-null backgrounds confirmed the pathway's necessity and sufficiency in mediating mutant SHP2's effects. Our data establish the developmental stage-specific effects of Q79R cardiac expression in NS; show that ablation of subsequent ERK1/2 activation prevents the development of cardiac abnormalities; and suggest that ERK1/2 modulation could have important implications for developing therapeutic strategies in CHD.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Chromosome Disorders / embryology
  • Chromosome Disorders / enzymology*
  • Chromosome Disorders / genetics
  • Chromosome Disorders / pathology
  • Chromosome Disorders / therapy
  • Disease Models, Animal
  • Gene Expression Regulation, Developmental / genetics
  • Gene Expression Regulation, Enzymologic / genetics
  • Heart Septal Defects, Ventricular / embryology
  • Heart Septal Defects, Ventricular / enzymology*
  • Heart Septal Defects, Ventricular / genetics
  • Heart Septal Defects, Ventricular / pathology
  • Heart Septal Defects, Ventricular / prevention & control
  • Heart Ventricles / embryology
  • Heart Ventricles / enzymology
  • Heart Ventricles / pathology
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • MAP Kinase Signaling System* / genetics
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Mutation, Missense
  • Myocytes, Cardiac / enzymology
  • Myocytes, Cardiac / pathology
  • Noonan Syndrome / embryology
  • Noonan Syndrome / enzymology*
  • Noonan Syndrome / genetics
  • Noonan Syndrome / pathology
  • Noonan Syndrome / therapy
  • Protein Phosphatase 2
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatases / biosynthesis*
  • Protein Tyrosine Phosphatases / genetics

Substances

  • Intracellular Signaling Peptides and Proteins
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Protein Phosphatase 2
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatases
  • Ptpn11 protein, mouse