Studies of the role of transcription factors have provided insights into the regulatory mechanisms that lead to cell-specific gene transcription and, as a result, control the differentiation of distinct cell lineages during development. The intestinal epithelium, because of its proliferative capacity, represents a continuous developmental system and therefore provides an attractive model to study biologically important processes. It also provides a unique opportunity for the identification and analysis of factors that control cell growth and differentiation. An in-depth understanding of the mechanisms which govern transcriptional regulation in intestinal epithelium therefore requires the identification and characterization of novel transcription factors which show a restricted pattern of expression. We have recently identified Intestinal-enriched Kruppel-Like Factor (IKLF;KLF5), a novel member of the Kruppel- like family (KLF) of transcription factors. IKLF is a zinc finger transcription factor which is highly expressed in epithelial cells of the intestinal crypts suggesting a role for IKLF in the proliferation and differentiation of crypt cells. In this application we propose to study the cell type specific expression of IKLF during development and in adult tissue, to develop a mouse model with targeted disruption of the IKLF gene and study the phenotypic consequences due to the lack of IKLF expression as a means of determining its biological function. Our studies are further designed to more fully describe the transcriptional regulation of IKLF expression, and identification of its downstream target gene(s). The proposed molecular and functional studies provide an opportunity to understand the biological role of IKLF in mediating intestine-specific gene expression as a means to further define the novel pathways important for the development and differentiation of intestinal tissue.
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