The long-term objective of this research is to gain a better understanding of the regulation of skin development. The goal of this project is to elucidate the function of Foxn1a member of the winged-helix/forkhead family of transcription factors. In rodents, the loss of Foxn1 function results in the nude phenotype, which is characterized by the abnormal morphogenesis of the skin, thymus, and mammary gland. From the project's work to date, the following model of Foxn1 function has been developed. In the skin, epithelial cells induce Foxn1 as they lose the ability to multiply and initiate terminal differentiation. Within the epithelium, Foxn1 then promotes up to three fundamental processes: the production of differentiated features, the coupling of cell division to differentiation, and the acquisition of melanin. To regulate these processes, Foxn1 activates intercellular signaling systems, thereby enabling epithelial cells to cooperate with each other and melanocytes. Thus, according to this model, Foxn1 acts as a regulatory link or nexus, coordinating the growth, differentiation, and pigmentation of cutaneous epithelia. To test this model, the downstream effectors of Foxn1 will be identified.
The specific aims of the project are as follows: 1) to isolate and characterize Foxnl effectors, 2) to determine the functional significance of the effectors in the Foxn1 pathway, and 3) to dissect the molecular mechanism by which Foxn1 regulates each effector. The project will use the mouse as an experimental system, taking advantage of existing Foxn1 transgenics as well as nude mutants. In humans, FOXN1 is conserved in its sequence and function, suggesting that the human and rodent proteins act via similar pathways. Thus, by identifying Foxn1's effectors, the project may provide insight into diseases associated with abnormal pigmentation, hyperproliferation, or aberrant differentiation.
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