(Verbatim) The global objective of this research is to elucidate the mechanisms underlying growth, differentiation and development in mammalian epidermis and hair. To achieve this goal, we are focusing on understanding the regulatory controls that govern the genes specifically and temporally expressed in these cells. Since keratin genes are differentially and abundantly transcribed in these cells, understanding how their complex pattern is established is key to elucidating how keratinocytes differentiate, and how these processes go awry in human skin diseases and cancers. Of particular interest is the regulation of K5 and K14, the major proteins of basal keratinocytes and stem cells. These cells are used in burn operations, and elucidating how K5 and K14 promoter activity is controlled is a prerequisite to developing keratinocytes as therapeutic agents for drug delivery and gene therapy. We have already identified some factors involved in controlling K5 and K14 transcription in vitro and in vivo, and we will now identify the remaining factors and determine their functional significance in combinatorially controlling keratinocyte-specific gene expression. A related issue is how pluripotent stem cells choose between an epidermal versus hair cell fate. We have discovered that Wnt signal transduction pathways are involved, implicating the Tcf3- and Lef1 - beta catenin transcription factor complexes at 4 times when key cell fate decisions are made by skin epithelial cells: a) when pluripotent ectoderm initiates follicle morphogenesis; b) when mesenchyme specializes to form the dermal component of follicles; c) when matrix cells differentiate to form hair shaft precursor cells and d) when pluripotent adult stem cells are triggered to initiate a new hair cycle. Identifying the external factors transmitting these signals, understanding how skin cells at these times selectively receive these cues, and elucidating the downstream tranducers of these signals will be important in understanding how pluripotency is maintained in the skin stem cell, how cell fate decisions are made, and how these processes are defective in congenital hair disorders, which are often severe and involve additional organs. We will focus on these issues and continue our now well-established tradition of applying our molecular genetic research to medicine.
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