The dorsal-ventral axis in the Drosophila embryo is established by an inductive cue originates in the somatic follicle cells that ensheathe the developing oocyte. This inductive cue requires the expression of the maternal effect locus pipe in the somatic tissue of the female. The activity of this gene contributes to defining the polarity of a signal transduction pathway that results in graded nuclear uptake of the dorsal gene product, a transcription factor. The broad, long-term objective of this proposal is to elucidate the molecular nature of the somatic inductive cue and how it functions and is regulated. These investigations have medical relevance in two respects. Drosophila embryonic dorsal- ventral polarity appears to result, at least in part, from extracellular regulation of serine proteolytic activity, similar to what is seen during blood clot formation and complement fixation in humans. Second, regulation of nuclear localization is a general mechanism for the regulation of transcription factors and the dorsal gene shares amino acid sequence homology with a number of vertebrate transcription factors whose activities are also regulated in this way. One of these, the transcription factor NF kappa B is an important transcriptional regulator of the immune system. To investigate the mechanism by which the somatic epithelium of the egg chamber controls embryonic dorsal-ventral polarity polarity the pipe gene will be cloned and characterized. Its nucleotide sequence will be determined and temporal and spatial patterns of expression of the RNA will be investigated. Antibodies directed against the pipe protein product will be obtained and immunohistochemistry will be used to investigate spatial and subcellular localization of the protein during dorsal-ventral pattern formation. To determine how the prior determination of dorsal-ventral polarity in the egg chamber influences embryonic dorsal-ventral polarity, the pipe RNA and protein expression patterns will also be investigated in the ovaries of females carrying mutations which alter the polarity of the egg chamber.
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