Kidney development is largely the result of a unique cellular transdifferentiation event wherein metanephric mesenchymal cells become epithelial cells which form the glomerulus and tubules of mature nephrons. These events are initiated by a poorly understood reciprocal inductive interaction between epithelial cells of the ureteric bud and the proliferating mesenchyme. These dramatic cellular differentiation events during nephrogenesis must require a considerable reprogramming of gene expression in the nucleus and therefore must be mediated in part by a set of kidney-specific transcription factors. However, little is currently known about transcription factors in the kidney which function specifically to mediate the mesenchymal-epithelial transition and/or maintain the differentiated phenotype. The forkhead domain family of transcription factors share a highly conserved approximately 110 amino acid motif which mediates sequence- specific DNA binding. Almost all known forkhead -domain containing genes function as regulators of development and pattern formation in early embryogenesis. We have obtained a novel forkhead domain transcription factor, MFH-1 (Mesenchyme Forkhead-1) and preliminary studies suggest that it is expressed in condensing metanephric mesenchyme at a critical stage in the mesenchymal-epithelial transition. Nothing is known of the structure/function or role in kidney development of MFH-1. In this proposal, we will perform a comprehensive developmental and biochemical analysis for MFH-I specifically, we will l) determine the spatio-temporal, cell-type-specific expression patterns in murine development and in the kidney organ culture system in vitro using high resolution in-situ hybridization and immunohistochemistry, 2) isolate and characterize the genomic clones/ promotor regions and localize genetic elements required for kidney-cell specific expression, 3) isolate the DNA binding sites recognized by MFH-1 protein and utilize this information to search for potential target genes, and 4) determine the biological consequences of ablating MFH-1 expression using antisense oligonucleotides in the kidney organ culture system and in established cell lines. This analysis should provide a comprehensive look at a novel forkhead domain transcription factor in murine kidney organogenesis and provide new insights into the regulation of differentiation during the nephrogenic process.
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