Mechanism of RNA Localization in Drosophila Development

Princeton University, Princeton NJ

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Abstract

DESCRIPTION (provided by applicant): Messenger RNA (mRNA) localization has emerged as an important mechanism for generating asymmetric protein distributions that promote morphological and functional cell polarization during development. Polarized cellular functions like motility in fibroblasts and synaptic plasticity in dendrites, asymmetric division of budding yeast, and embryonic axis formation in Xenopus and Drosophila all require proteins that are synthesized from localized mRNAs. To date, investigations of mRNA localization have focused on a relatively small number of mRNAs in select cell types. However, a recent study uncovered over 1500 transcripts with distinct subcellular distributions in the Drosophila embryonic epithelium, indicating that mRNA localization is far more prevalent than previously thought. The full repertoire of mRNAs that undergo localization in specialized, morphologically complex cells is not known, however. This competitive revision application, in response to NOT-OD-09-058: "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications", proposes to test the hypothesis that numerous mRNAs are localized in a diversity of specialized cell types through a novel genome wide-screen for transcripts with asymmetric subcellular distributions. This major new objective expands the scope of the currently funded grant (R01 GM067758), which focuses on elucidating mechanisms of mRNA localization using Drosophila nanos mRNA as a model. The screen combines a method developed in the lab for in vivo fluorescent labeling of mRNAs with well established methods for gene trapping and tissue specific gene expression. The initial screen will focus on neuronal cells but, in the future, can be expanded to other cell types. Identification of mRNAs with tissue-specific polarized distributions will not only provide insight into cellular morphogenetic mechanisms but will also provide a data-base for bioinformatic analysis to discern cis-acting sequences and/or structural motifs that govern localized mRNA distributions. PUBLIC HEALTH RELEVANCE: Messenger RNA localization produces localized protein distributions required for embryonic axis formation and asymmetric cell division during development and for polarized cellular functions like motility in fibroblasts and synaptic plasticity in dendrites. Altered regulation of messenger RNAs that undergo localization in differentiated cells have been associated with a variety of cancers as well as neuronal defects and may reflect roles for messenger RNA localization in cell fate specification, cell polarity, and migration. The proposed studies will shed light on mechanisms by which localized mRNAs control of basic cellular morphogenetic processes needed for development, growth, and differentiation and how the disruption of these processes may lead to diseases like cancer or neurological dysfunction.