Mechanisms of RNA localization in oocytes

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 DESCRIPTION (provided by applicant): Establishment of polarity in the egg can be viewed as the earliest step in embryonic patterning. Thus, differences in cell fate among the early cleavage cells are a consequence of asymmetric distributions of informational molecules in the egg cytoplasm before fertilization. In a wide variety of organisms, the basis for such polarity can be provided by localized maternal determinants in the form of mRNA. Among vertebrates, Vg1 mRNA is a prominent example of a localized mRNA that plays a role in embryonic patterning. Restricted expression of Vg1 protein in the vegetal hemisphere of the egg is critical for correct patterning of the embryo, making localization of Vg1 mRNA an important model for understanding how maternal molecules are localized to influence pattern and polarity. The goal of this research project is to investigate the mechanisms that direct targeting of mRNAs to specific regions of the cell cytoplasm to generate cell and developmental polarity. The foundation for this investigation has been laid by our progress studying the molecular pathway that directs maternal mRNA molecules to the vegetal cortex of the Xenopus oocyte. Through development of approaches to track mRNA transport in live oocytes and biochemical strategies to isolate transport complexes, our experiments have uncovered new steps in the pathway and revealed new components of the cellular transport machinery. Our current proposal seeks to capitalize on these findings in order to delineate the molecular pathway that orchestrates delivery of maternal mRNAs to their cytoplasmic destinations. Three specific aims are proposed: In Aim 1, we will analyze the molecular interactions that drive vegetal RNP transport granule assembly, in Aim 2, we will determine the mechanisms that regulate directionality during RNA transport and in Aim 3 we will investigate the mechanisms that control retention of localized RNAs at the oocyte cortex. The proposed research is designed to reveal the mechanisms by which mRNA molecules are transported within cells to generate spatially restricted protein expression, and will provide insight into how developmental signals are spatially distributed in the vertebrate embryo. This work will impact issues related to human health such as birth defects, as well as neurological diseases that have been linked to defective RNA transport and localized protein synthesis.