PUBLICATION
Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors
- Authors
- Anastasaki, C., Estep, A.L., Marais, R., Rauen, K.A., and Patton, E.E.
- ID
- ZDB-PUB-090422-19
- Date
- 2009
- Source
- Human molecular genetics 18(14): 2543-2554 (Journal)
- Registered Authors
- Patton, E. Elizabeth
- Keywords
- none
- MeSH Terms
-
- Male
- Small Molecule Libraries/pharmacology*
- Genetic Diseases, Inborn/embryology
- Genetic Diseases, Inborn/enzymology*
- Genetic Diseases, Inborn/genetics
- MAP Kinase Signaling System/drug effects*
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/growth & development*
- Zebrafish/metabolism
- Enzyme Activation/drug effects
- Mitogen-Activated Protein Kinase Kinases/genetics
- Mitogen-Activated Protein Kinase Kinases/metabolism*
- Proto-Oncogene Proteins B-raf/genetics
- Proto-Oncogene Proteins B-raf/metabolism*
- Alleles
- Animals
- Disease Models, Animal
- Humans
- PubMed
- 19376813 Full text @ Hum. Mol. Genet.
Citation
Anastasaki, C., Estep, A.L., Marais, R., Rauen, K.A., and Patton, E.E. (2009) Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors. Human molecular genetics. 18(14):2543-2554.
Abstract
The Ras/MAPK pathway is critical for human development, and plays a central role in the formation and progression of most cancers. Children born with germ-line mutations in BRAF, MEK1 or MEK2 develop cardio-facio-cutaneous (CFC) syndrome, an autosomal dominant syndrome characterized by a distinctive facial appearance, heart defects, skin and hair abnormalities, and mental retardation. CFC syndrome mutations in BRAF promote both kinase-activating and kinase-impaired variants. CFC syndrome has a progressive phenotype, and the availability of clinically active inhibitors of the MAPK pathway prompts the important question as to whether such inhibitors might be therapeutically effective in treatment of CFC syndrome. To study the developmental effects of CFC mutant alleles in vivo, we have expressed a panel of 28 BRAF and MEK alleles in zebrafish embryos to assess the function of human disease alleles and available chemical inhibitors of this pathway. We find that both kinase-activating and kinase-impaired CFC mutant alleles promote the equivalent developmental outcome when expressed during early development, and that treatment of CFC-zebrafish embryos with inhibitors of the FGF-MAPK pathway can restore normal early development. Importantly, we find a developmental window in which treatment with a MEK inhibitor can restore the normal early development of the embryo, without the additional, unwanted developmental effects of the drug.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping