The goal of this research is to understand the role of the pie-1 gene in the specification of the C. elegans germ cell lineage. During C. elegans embryogenesis a series of four divisions gives rise to a single precursor of the PIE-1 protein entire germline. This germ cell precursor divides just once more during embryogenesis and then arrests division until after hatching. The pie-1 gene is required for the proper specification of the germ cell lineage; in pie-1 mutants descendants of the germ cell precursor continue to divide and differentiate as somatic cells. Recent findings indicate that pie-1 encodes a nuclear protein that is localized exclusively to the germ cell precursor throughout the early cleavages in the C. elegans embryo, (pie-1 is both nuclear and cytoplasmic at the 2- and 4-cell stage, see diagram). The pie-1 protein contains two """"""""zinc finger"""""""" motifs found in a family of mammalian """"""""immediate early"""""""" growth factor response genes. Genetic studies suggest that pie-1 negatively regulates somatic differentiation in the germ cell precursor, possibly by functioning as a transcriptional repressor. Consistent with this model, expression of pie-1 in human cells appears to be sufficient to repress the activity of some but not all transcription factors. The proposed research uses molecular and classical genetic approaches to address the function and regulation of pie-1. The mechanism of pie-1 localization, and the developmental consequences of its mislocalization will be determined. Functional domains necessary for pie-1 activity will be identified through systematic in-vitro mutagenesis, followed by functional analysis in both human soma cells and C. elegans. A yeast two hybrid screen and genetic studies in C. elegans will be used to identify interacting genes. These experiments will elucidate the role of pie-1 in the initial steps of embryonic patterning in C. elegans. Examining the function of pie-1 and interacting genes in this relatively simple and easily manipulated genetic system may shed light on the possible role of related genes in the control of transcription and development in other organisms including humans.
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