Messenger RNA localization plays a key role in creating the asymmetric distributions of proteins necessary for cellular and developmental polarity. Impairment of mRNA localization pathways has been implicated in human diseases such as spinal muscular atrophy and fragile X syndrome and targeting of mRNAs to cancer cell protrusions suggests a role in metastasis. The sorting of specific mRNAs to different subcellular domains is a complex process involving the assembly and trafficking of ribonucleoprotein particles (RNPs). How specificity is conferred on this process, particularly in cells where many mRNAs are localized concurrently, is poorly understood. This proposal integrates biochemical, genetic, and quantitative and live imaging-based approaches to investigate how different mRNAs are specifically recognized to form localization competent RNPs and assembled into higher order, functional RNA granules.
Aims 1 and 2 address the end masse localization of numerous transcripts to the germ plasm at the posterior of the Drosophila oocyte and their differential inheritance by germ cell progenitors. This system affords an ideal opportunity to investigate the molecular mechanisms that regulate the formation, composition, and behavior of RNPs essential for localization and function in generating asymmetry.
Aim 3 capitalizes on our recent identification of a large number of localized RNAs in Drosophila sensory neuron dendrites. The major goals of this aim are to critically assess the functional significance of RNA localization in neurons and to probe the generality of the mechanistic principles emerging from Aims 1 and 2.
Messenger RNA localization is a widely used mechanism for producing proteins in particular regions of cells where their functions are needed and plays a well-documented role in animal development and in the formation and function of polarized cells like neurons. Impairment of mRNA localization pathways has been implicated in human diseases such as spinal muscular atrophy and fragile X syndrome and localization of mRNAs to cancer cell protrusions may be important in metastasis. The proposed studies will shed light on the mechanisms used to direct mRNAs to their specific destinations and how the disruption of this process may lead to diseases like cancer or neurological dysfunction.
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