Inducible expression of (V600E) Braf using tyrosinase-driven Cre recombinase results in embryonic lethality.
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.
Dhomen
Nathalie
N
The Institute of Cancer Research, Signal Transduction Team, Cancer Research UK Centre for Cell and Molecular Biology, London, UK.
Da Rocha Dias
Silvy
S
Hayward
Robert
R
Ogilvie
Lesley
L
Hedley
Douglas
D
Delmas
Veronique
V
McCarthy
Afshan
A
Henderson
Deborah
D
Springer
Caroline J
CJ
Pritchard
Catrin
C
Larue
Lionel
L
Marais
Richard
R
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
D014442:Monophenol Monooxygenase; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; C045073:Cre recombinase; D019426:Integrases