Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors.
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 the 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.
Anastasaki
Corina
C
MRC Human Genetics Unit and The University of Edinburgh Institute for Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
Estep
Anne L
AL
Marais
Richard
R
Rauen
Katherine A
KA
Patton
E Elizabeth
EE
D000483:Alleles; D000818:Animals; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D030342:Genetic Diseases, Inborn / Q000196:embryology / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism
D054852:Small Molecule Libraries; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases