Elucidating the mechanisms which underlie the generation of diverse cell types during mammalian development remains a central problem in biology. Recent experiments have suggested that tissue restricted transcription factors, and their modification by signaling pathways, play a crucial role in organ development. During embryogenesis, cells of the somatic ectoderm have several different fates. Among the tissues that form are the anterior pituitary gland, breast, epidermis, hair and nails. We have recently identified a POU domain gene, Skin-1a/i (Skn-1a/i), that is activated in somatic ectoderm during its commitment to epidermis, and encodes for two distinct transcripts, referred to as Skn-1a and Skn-1i. Based on the important roles that members of the POU domain gene family play in development of other organs, as well as the skin-restricted expression of the Skn-1a/i gene, we propose that Skn-1 plays a role in epidermal differentiation. This hypothesis is further supported by experiments indicating that Skn-1a can activate two promoters associated with epidermal differentiation, the keratin 10 and HPV1A long control region. In this application, I propose to begin testing the role of the Skn-1a/i gene in epidermal differentiation. Specifically, I propose: 1. To determine the expression pattern of Skn-1a and Skn-1i during normal mouse development. 2. To characterize the regulation of Skn-1a/i and other octamer binding transcription factors during differentiation of cultured keratinocytes in vitro. 3. To generate and analyze mice deficient for the Skn-1a/i genomic locus. The proposed research uses biochemical and genetic methods to gain insights into the mechanisms of cellular differentiation in epidermis. Abnormal differentiation of keratinocytes is a prominent feature of many skin diseases and therefore this work is likely to yield information applicable to both normal skin development as well as skin diseases.
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| Andersen, B; Weinberg, W C; Rennekampff, O et al. (1997) Functions of the POU domain genes Skn-1a/i and Tst-1/Oct-6/SCIP in epidermal differentiation. Genes Dev 11:1873-84 |
