RRC ID 30833
Author Inoue S, Moriya M, Watanabe Y, Miyagawa-Tomita S, Niihori T, Oba D, Ono M, Kure S, Ogura T, Matsubara Y, Aoki Y.
Title New BRAF knockin mice provide a pathogenetic mechanism of developmental defects and a therapeutic approach in cardio-facio-cutaneous syndrome.
Journal Hum Mol Genet
Abstract Cardio-facio-cutaneous (CFC) syndrome is one of the 'RASopathies', a group of phenotypically overlapping syndromes caused by germline mutations that encode components of the RAS-MAPK pathway. Germline mutations in BRAF cause CFC syndrome, which is characterized by heart defects, distinctive facial features and ectodermal abnormalities. To define the pathogenesis and to develop a potential therapeutic approach in CFC syndrome, we here generated new knockin mice (here Braf(Q241R/+)) expressing the Braf Q241R mutation, which corresponds to the most frequent mutation in CFC syndrome, Q257R. Braf(Q241R/+) mice manifested embryonic/neonatal lethality, showing liver necrosis, edema and craniofacial abnormalities. Histological analysis revealed multiple heart defects, including cardiomegaly, enlarged cardiac valves, ventricular noncompaction and ventricular septal defects. Braf(Q241R/+) embryos also showed massively distended jugular lymphatic sacs and subcutaneous lymphatic vessels, demonstrating lymphatic defects in RASopathy knockin mice for the first time. Prenatal treatment with a MEK inhibitor, PD0325901, rescued the embryonic lethality with amelioration of craniofacial abnormalities and edema in Braf(Q241R/+) embryos. Unexpectedly, one surviving pup was obtained after treatment with a histone 3 demethylase inhibitor, GSK-J4, or NCDM-32b. Combination treatment with PD0325901 and GSK-J4 further increased the rescue from embryonic lethality, ameliorating enlarged cardiac valves. These results suggest that our new Braf knockin mice recapitulate major features of RASopathies and that epigenetic modulation as well as the inhibition of the ERK pathway will be a potential therapeutic strategy for the treatment of CFC syndrome.
Volume 23(24)
Pages 6553-66
Published 2014-12-15
DOI 10.1093/hmg/ddu376
PII ddu376
PMID 25035421
MeSH Animals Benzamides / pharmacology* Benzazepines / pharmacology* Diphenylamine / analogs & derivatives* Diphenylamine / pharmacology Disease Models, Animal Drug Synergism Ectodermal Dysplasia / drug therapy* Ectodermal Dysplasia / genetics* Ectodermal Dysplasia / metabolism Ectodermal Dysplasia / pathology Embryo, Mammalian Facies Failure to Thrive / drug therapy* Failure to Thrive / genetics* Failure to Thrive / metabolism Failure to Thrive / pathology Female Gene Expression Regulation Gene Knock-In Techniques Genes, Lethal Heart Defects, Congenital / drug therapy* Heart Defects, Congenital / genetics* Heart Defects, Congenital / metabolism Heart Defects, Congenital / pathology Histone Deacetylase Inhibitors / pharmacology Histone Demethylases / antagonists & inhibitors Histone Demethylases / genetics Histone Demethylases / metabolism Humans Liver / abnormalities Liver / drug effects MAP Kinase Kinase Kinases / antagonists & inhibitors MAP Kinase Kinase Kinases / genetics MAP Kinase Kinase Kinases / metabolism Male Mice Mice, Transgenic Mutation Myocardium / pathology Protein Kinase Inhibitors / pharmacology Proto-Oncogene Proteins B-raf / genetics* Proto-Oncogene Proteins B-raf / metabolism Pyrimidines / pharmacology* Signal Transduction Skull / abnormalities Skull / drug effects
IF 5.101
Times Cited 33
Mice RBRC01828