BRAF knock-in mice provide a pathogenetic mechanism of developmental defects in CFC syndrome

2014 Fiscal Year Final Research Report

• Project/Area Number: 25860839
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Tohoku University
• Principal Investigator: INOUE SHINICHI 東北大学, 医学(系)研究科(研究院), 助教 (70622091)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: CFC症候群 / BRAF / RASopathies / RAS/MAPK / 先天性心疾患 / ヒストン脱メチル化酵素

Outline of Final Research Achievements

Germline mutations in BRAF cause cardio-facio-cutaneous (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 generated knock-in mice expressing the Braf Q241R mutation. Knock-in mice manifested embryonic/neonatal lethality, showing liver necrosis, edema, craniofacial abnormalities and multiple heart defects. Prenatal treatment with a MEK inhibitor, PD0325901, or a histone 3 demethylase inhibitor, GSK-J4, rescued the embryonic lethality in knock-in embryos. Combination treatment with PD0325901 and GSK-J4 further increased the rescue from embryonic lethality. These results suggest that Braf knock-in mice recapitulate major features of CFC syndrome 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.

Free Research Field

医歯薬学