Abstract: The thickened epidermis of palmoplantar (sole and palm) skin expresses a unique combination of structural proteins that contribute to its superior resistance to biomechanical stress. PP skin is also hypo-pigmented when compared with adjacent skin, is hairless and exhibits a high density of eccrine sweat glands (EG). Prior research demonstrates that regional specific differentiation of the epidermis is imposed on keratinocytes during embryonic/perinatal development but that once specified, keratinocytes develop an intrinsic epigenetic memory of their site of origin. Grafting and culture experiments suggest that this memory is incomplete, and that signaling from orthotopic dermis sustains and augments appropriate PP differentiation, while signals from heterotopic dermis can promote alternative differentiation. These studies have been hampered by reliance on a limited set of markers. The work proposed here employs genetically modified mice to create a comprehensive molecular description of sole- specific epidermal differentiation by RNAseq and identify inductive signals from the dermis that promote that differentiation during development. Inducible gain and loss of function of genes that generate bi-dorsal and bi-ventral feet are used to explore the extent to which the inductive signals that specify regional keratinocyte identity in the sole are required to maintain site-specific epidermal differentiation in the adult. We also ask whether manipulation of those signals in intact skin can provoke epidermis in other regions of the body to adopt aspects of sole epidermal character. Successful completion of this work will settle controversies about the relative weight of intrinsic keratinocyte characteristics vs. ongoing inductive signaling from dermis in intact adult skin. It is designed to provide insights that may lead to novel approaches to conferring superior performance on patient skin that has been forced to assume load-bearing duties, for example when leg amputation imposes this function on more proximal limb skin.