A New System to Study the Control of Epidermal Growth

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DESCRIPTION (provided by applicant): Precise temporal control of epidermal differentiation is essential for proper formation of the skin. Disruptions to this process can result in a variety of skin diseases and tumorigenesis. For example, premature and delayed differentiation within the epidermis can lead to hyperplasias associated with psoriasis, and signals from the underlying dermis can establish when aberrant keratinocytes form in association with squamous carcinomas. Thus, identifying cellular and molecular mechanisms that control the timing of epidermal differentiation is a prerequisite for understanding the causes of skin disorders and for devising innovative treatment strategies. This proposal will assess the feasibility of utilizing a new avian chimeric system to identify molecular mechanisms by which the neural crest-derived dermis regulates epidermal development, and to develop novel therapeutic approaches for controlling the timing of epidermal differentiation. Quail and duck embryos have divergent growth rates, and following transplantation, quail donor neural crest cells, which give rise to the craniofacial dermis, induce premature formation of host epidermal structures such as feathers by accelerating the expression of genes including members of the Bone Morphogenetic Protein (BMP) signaling pathway. Conversely in reciprocal transplants, duck donor dermis delays the timing of host epidermal gene expression and retards feather histogenesis. We hypothesize that neural crest-derived mesenchyme controls the timing of feather morphogenesis by regulating BMP signaling between the dermis and epidermis. To test our hypothesis we will combine the quail-duck chimeric system, which produces premature feather buds in quck (quail donor dermis, duck host epidermis) and delayed feather buds in duail (duck donor dermis, quail host epidermis) with molecular approaches that will specifically modulate BMP signaling in donor dermis and/or host-derived epidermis. Our immediate goal is to "rescue" the premature or delayed development of the epidermis in chimeras, which has potential clinical implications for devising molecular-based therapies to treat skin disorders that have as their etiology a disruption to the timing of epidermal differentiation. While this proposal is exploratory in nature, a long-term goal is to create a potent experimental paradigm for addressing numerous critical issues in epidermal development such as those that relate to the regulation of cell proliferation, melanogenesis, and keratinization.