Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation.
Noonan syndrome is a common human autosomal dominant birth defect, characterized by short stature, facial abnormalities, heart defects and possibly increased risk of leukemia. Mutations of Ptpn11 (also known as Shp2), which encodes the protein-tyrosine phosphatase Shp2, occur in approximately 50% of individuals with Noonan syndrome, but their molecular, cellular and developmental effects, and the relationship between Noonan syndrome and leukemia, are unclear. We generated mice expressing the Noonan syndrome-associated mutant D61G. When homozygous, the D61G mutant is embryonic lethal, whereas heterozygotes have decreased viability. Surviving Ptpn11(D61G/+) embryos ( approximately 50%) have short stature, craniofacial abnormalities similar to those in Noonan syndrome, and myeloproliferative disease. Severely affected Ptpn11(D61G/+) embryos ( approximately 50%) have multiple cardiac defects similar to those in mice lacking the Ras-GAP protein neurofibromin. Their endocardial cushions have increased Erk activation, but Erk hyperactivation is cell and pathway specific. Our results clarify the relationship between Noonan syndrome and leukemia and show that a single Ptpn11 gain-of-function mutation evokes all major features of Noonan syndrome by acting on multiple developmental lineages in a gene dosage-dependent and pathway-selective manner.
Pubmed ID: 15273746 RIS Download
Animals | Cell Lineage | Craniofacial Abnormalities | Disease Models, Animal | Endocardial Cushion Defects | Flow Cytometry | Gene Dosage | Genes, Dominant | Heart Defects, Congenital | Immunohistochemistry | Intracellular Signaling Peptides and Proteins | Mice | Mice, Mutant Strains | Mitogen-Activated Protein Kinases | Mutation | Myeloproliferative Disorders | Noonan Syndrome | Precipitin Tests | Protein Tyrosine Phosphatase, Non-Receptor Type 11 | Protein Tyrosine Phosphatases