title: Inducible expression of (V600E) Braf using tyrosinase-driven Cre recombinase results in embryonic lethality.
abstract: We recently demonstrated that expression of (V600E)Braf in mature mouse melanocytes induces melanoma. Here, we show that expression of (V600E)Braf using the tyrosinase promoter leads to an unexpected embryonic lethality, with the animals dying before, at, or shortly after birth. The mice suffer from a range of developmental defects in the skin, the brain, the eyes and the heart, tissues that are normally colonized by melanocytes. We show that the (V600E)Braf expressing cells are potential melanocytic precursors that are fully transformed, suggesting that (V600E)Braf stimulates proliferation and blocks differentiation of these cells. Our data suggests that the presence of these cells in the organs that are normally occupied by melanocytes leads to severe developmental disruption, resulting in catastrophic defects and leading to death of the individual.
authors.affiliation: The Institute of Cancer Research, Signal Transduction Team, Cancer Research UK Centre for Cell and Molecular Biology, London, UK.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dhomen
authors.forename: Silvy
authors.initials: S
authors.lastname: Da Rocha Dias
authors.forename: Robert
authors.initials: R
authors.lastname: Hayward
authors.forename: Lesley
authors.initials: L
authors.lastname: Ogilvie
authors.forename: Douglas
authors.initials: D
authors.lastname: Hedley
authors.forename: Veronique
authors.initials: V
authors.lastname: Delmas
authors.forename: Afshan
authors.initials: A
authors.lastname: McCarthy
authors.forename: Deborah
authors.initials: D
authors.lastname: Henderson
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Springer
authors.forename: Catrin
authors.initials: C
authors.lastname: Pritchard
authors.forename: Lionel
authors.initials: L
authors.lastname: Larue
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D000013:Congenital Abnormalities / Q000235:genetics* / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D055879:Gene Knock-In Techniques; D005804:Genes, Lethal / Q000235:genetics*; D019426:Integrases / Q000235:genetics; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D014442:Monophenol Monooxygenase / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism
chemical_list: D014442:Monophenol Monooxygenase; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; C045073:Cre recombinase; D019426:Integrases