PUBLICATION
Phosphatase-Dependent and -Independent Functions of Shp2 in Neural Crest Cells Underlie LEOPARD Syndrome Pathogenesis
- Authors
- Stewart, R.A., Sanda, T., Widlund, H.R., Zhu, S., Swanson, K.D., Hurley, A.D., Bentires-Alj, M., Fisher, D.E., Kontaridis, M.I., Look, A.T., and Neel, B.G.
- ID
- ZDB-PUB-100525-19
- Date
- 2010
- Source
- Developmental Cell 18(5): 750-762 (Journal)
- Registered Authors
- Look, A. Thomas, Stewart, Rodney A., Zhu, Shizhen
- Keywords
- DEVBIO, HUMDISEASE
- MeSH Terms
-
- Animals
- Cell Differentiation
- Cell Division
- Cell Movement
- Cell Survival
- Gastrula/physiology
- Germ-Line Mutation*
- Humans
- LEOPARD Syndrome/genetics
- LEOPARD Syndrome/pathology
- Neural Crest/physiology
- Neural Tube/physiology
- Noonan Syndrome/genetics
- Noonan Syndrome/pathology
- Protein Tyrosine Phosphatase, Non-Receptor Type 1/genetics
- Protein Tyrosine Phosphatase, Non-Receptor Type 1/physiology*
- Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics
- RNA, Messenger/genetics
- Transcription, Genetic
- Zebrafish/embryology
- Zebrafish/genetics
- PubMed
- 20493809 Full text @ Dev. Cell
Citation
Stewart, R.A., Sanda, T., Widlund, H.R., Zhu, S., Swanson, K.D., Hurley, A.D., Bentires-Alj, M., Fisher, D.E., Kontaridis, M.I., Look, A.T., and Neel, B.G. (2010) Phosphatase-Dependent and -Independent Functions of Shp2 in Neural Crest Cells Underlie LEOPARD Syndrome Pathogenesis. Developmental Cell. 18(5):750-762.
Abstract
The tyrosine phosphatase SHP2 (PTPN11) regulates cellular proliferation, survival, migration, and differentiation during development. Germline mutations in PTPN11 cause Noonan and LEOPARD syndromes, which have overlapping clinical features. Paradoxically, Noonan syndrome mutations increase SHP2 phosphatase activity, while LEOPARD syndrome mutants are catalytically impaired, raising the possibility that SHP2 has phosphatase-independent roles. By comparing shp2-deficient zebrafish embryos with those injected with mRNA encoding LEOPARD syndrome point mutations, we identify a phosphatase- and Erk-dependent role for Shp2 in neural crest specification and migration. We also identify an unexpected phosphatase- and Erk-independent function, mediated through its SH2 domains, which is evolutionarily conserved and prevents p53-mediated apoptosis in the brain and neural crest. Our results indicate that previously enigmatic aspects of LEOPARD syndrome pathogenesis can be explained by the combined effects of loss of Shp2 catalytic function and retention of an SH2 domain-mediated role that is essential for neural crest cell survival.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping