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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2014
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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. |
format | Online Article Text |
id | pubmed-4289449 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
record_format | MEDLINE/PubMed |
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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