title: Fate and plasticity of the epidermis in response to congenital activation of BRAF.
abstract: Germline and somatic mutations in RAS and its downstream effectors are found in several congenital conditions affecting the skin. Here we demonstrate that activation of BRAF in the embryonic mouse ectoderm triggers both craniofacial and skin defects, including hyperproliferation, loss of spinous and granular keratinocyte differentiation, and cleft palate. RNA sequencing of the epidermis confirmed these findings but unexpectedly revealed evidence of continued epidermal maturation, expression of >80% of epidermal differentiation complex genes, and formation of a hydrophobic barrier. Spinous and granular differentiation were restored by pharmacologic inhibition of MAPK/ERK kinase or BRAF. However, restoration of epidermal differentiation was non-cell autonomous and required dermal tissue to be present in tissue recombination studies. These studies indicate that early activation of the RAF signaling pathway in the ectoderm has effects on specific steps of epidermal differentiation, which may be amenable to treatment with currently available pharmacologic inhibitors.
authors.affiliation: Division of Dermatology, Department of Medicine, Institute for Genomic Medicine, Stem Cell Program, University of California, San Diego, La Jolla, California, USA.
authors.forename: Suguna R
authors.initials: SR
authors.lastname: Krishnaswami
authors.affiliation: Division of Dermatology, Department of Medicine, Institute for Genomic Medicine, Stem Cell Program, University of California, San Diego, La Jolla, California, USA.
authors.forename: Shantanu
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Next Generation Sequencing Core, The Scripps Research Institute, San Diego, California, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Ordoukhanian
authors.affiliation: Division of Dermatology, Department of Medicine, Institute for Genomic Medicine, Stem Cell Program, University of California, San Diego, La Jolla, California, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Yu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D004475:Ectoderm / Q000378:metabolism; D004789:Enzyme Activation; D004817:Epidermis / Q000196:embryology*; D005260:Female; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D011247:Pregnancy; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology
chemical_list: C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins