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 expression of keratins, the major structural proteins of these cells. There are > 15 keratin genes that are differentially expressed at various stages of epidermal and follicle differentiation. Understanding how this complex pattern of keratin gene expression is established is therefore key to understanding how these cells develop and differentiate, and how these processes go awry in human skin diseases and cancers. The 5' keratin gene sequences are often sufficient to faithfully drive cell type and differentiation-specific expression in transgenic mice. We are particularly interested in understanding gene regulation of keratins K5 and K14, because they are the major proteins of basal keratinocytes. Due to their enormous proliferative capacity in culture, these cells have been used successfully for burn operations and are potentially powerful vehicles for drug delivery and gene therapy. Elucidating how KS and K14 promoter activity is controlled will be key in developing keratinocytes as therapeutic agents. We have already identified some important transcription factors involved in controlling KS and K14 gene expression in vitro and in vivo. The AP2 family of proteins bind to most keratinocyte-specific genes, and although they are not sufficient, they seem to be important for keratinocyte- specific gene expression. It is now essential that we explore further the functional significance of multiple AP2 genes in keratinocyte development and differentiation, and that we identify additional factors that are central to this process. A related issue is how the basal keratinocyte switches its program of gene expression when it commits to terminally differentiate. Through the use of dominant negative retinoic acid receptor mutants, we have discovered that retinoids control this switch. We are now within reach of identifying the downstream receptor target genes that are key to controlling early stages of differentiation. This knowledge is a fundamental prerequisite to understanding why retinoids are useful in treating a variety of skin diseases, and how they exert their effects on skin. Finally, we are interested in how embryonic cells choose between an epidermal vs. hair cell fate, and we have shown that a transcription factor, LEF-1, is essential for hair follicle morphogenesis and gene expression. Identifying the upstream and downstream members in the LEF-1 pathway will be important in understanding how this process is defective in congenital hair disorders, which are often severe and involve additional organs. Our laboratory has recently pioneered research that illustrates how an understanding of skin proteins can lead us to the genetic bases of human skin disorders. In the coming years, we will continue our endeavors to apply our molecular genetic research to medicine.
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