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 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.