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Fate and plasticity of the epidermis in response to congenital activation of BRAF

Determining the developmental consequences of activated RAS and its downstream effectors is critical to understanding several congenital conditions caused by either germline or somatic mutations of the RAS pathway. Here we demonstrate that embryonic activation of BRAF in mouse ectoderm triggers both...

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Autores principales: Krishnaswami, Suguna R., Kumar, Shantanu, Ordoukhanian, Phillip, Yu, Benjamin D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289449/
https://www.ncbi.nlm.nih.gov/pubmed/25202828
http://dx.doi.org/10.1038/jid.2014.388
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author Krishnaswami, Suguna R.
Kumar, Shantanu
Ordoukhanian, Phillip
Yu, Benjamin D.
author_facet Krishnaswami, Suguna R.
Kumar, Shantanu
Ordoukhanian, Phillip
Yu, Benjamin D.
author_sort Krishnaswami, Suguna R.
collection PubMed
description Determining the developmental consequences of activated RAS and its downstream effectors is critical to understanding several congenital conditions caused by either germline or somatic mutations of the RAS pathway. Here we demonstrate that embryonic activation of BRAF in mouse ectoderm triggers both craniofacial and skin defects, including hyperproliferation, loss of spinous and granular keratinocyte differentiation, and cleft palate. RNA-sequencing reveals that despite an apparent block in spinous and granular differentiation, the epidermis continues to mature, expressing >80% of EDC genes and forming a hydrophobic barrier, both characteristic of later stages in epidermal development. Spinous and granular differentiation can be restored by pharmacologic inhibition of MEK or BRAF; however, in tissue recombination studies, phenotypic reversion was found to be non-cell autonomous and required dermal tissue to be present. These studies indicate that early activation of the RAF signaling pathway in the ectoderm has specific effects on progressive differentiation of the epidermis, which may be amendable to treatment using existing pharmacologic inhibitors.
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spelling pubmed-42894492015-08-01 Fate and plasticity of the epidermis in response to congenital activation of BRAF Krishnaswami, Suguna R. Kumar, Shantanu Ordoukhanian, Phillip Yu, Benjamin D. J Invest Dermatol Article Determining the developmental consequences of activated RAS and its downstream effectors is critical to understanding several congenital conditions caused by either germline or somatic mutations of the RAS pathway. Here we demonstrate that embryonic activation of BRAF in mouse ectoderm triggers both craniofacial and skin defects, including hyperproliferation, loss of spinous and granular keratinocyte differentiation, and cleft palate. RNA-sequencing reveals that despite an apparent block in spinous and granular differentiation, the epidermis continues to mature, expressing >80% of EDC genes and forming a hydrophobic barrier, both characteristic of later stages in epidermal development. Spinous and granular differentiation can be restored by pharmacologic inhibition of MEK or BRAF; however, in tissue recombination studies, phenotypic reversion was found to be non-cell autonomous and required dermal tissue to be present. These studies indicate that early activation of the RAF signaling pathway in the ectoderm has specific effects on progressive differentiation of the epidermis, which may be amendable to treatment using existing pharmacologic inhibitors. 2014-09-09 2015-02 /pmc/articles/PMC4289449/ /pubmed/25202828 http://dx.doi.org/10.1038/jid.2014.388 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Krishnaswami, Suguna R.
Kumar, Shantanu
Ordoukhanian, Phillip
Yu, Benjamin D.
Fate and plasticity of the epidermis in response to congenital activation of BRAF
title Fate and plasticity of the epidermis in response to congenital activation of BRAF
title_full Fate and plasticity of the epidermis in response to congenital activation of BRAF
title_fullStr Fate and plasticity of the epidermis in response to congenital activation of BRAF
title_full_unstemmed Fate and plasticity of the epidermis in response to congenital activation of BRAF
title_short Fate and plasticity of the epidermis in response to congenital activation of BRAF
title_sort fate and plasticity of the epidermis in response to congenital activation of braf
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289449/
https://www.ncbi.nlm.nih.gov/pubmed/25202828
http://dx.doi.org/10.1038/jid.2014.388
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