Small RNAs in Neurons

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DESCRIPTION (provided by applicant): Regulatory RNAs are important mediators of gene expression in eukaryotic cells. BC RNAs, a neuronal subtype of regulatory RNAs, are translational repressors that have been implicated in the control of local protein synthesis at the synapse. On-site translational control of gene expression is now seen as one of the major mechanisms underlying the long-term structural and functional plasticity of synaptic connections. A key requisite for the local translational control pathway in neurons is the selective delivery of various RNA components, in particular of regulatory RNAs, to diverse postsynaptic target sites within neuronal dendritic arborizations. How is such targeted delivery specified by RNAs, and how is it modulated by physiological stimuli and/or man-made drugs? In the research project proposed here, it is hypothesized that neuronal BC RNAs use architectural motifs to convey spatial information. It is suggested that such motifs specify differential destination sites in synapto-dendritic neuronal domains. It is the main objective of the present proposal to test this hypothesis by deciphering spatial information coding in neuronal BC RNAs. In the first part of the project, it is planned to conduct a functional dissection of differential dendritic targeting competence in BC RNAs. RNA motifs will be identified that direct constitutive and conditional dendritic targeting, respectively. The second part of the project will focus on modulation of RNA spatial coding in neurons. It is planned to establish whether dendritic RNA targeting mechanisms are subject to regulation by receptor stimulation, and whether man-made drugs impact and modulate these mechanisms. In summary, the planned research is directed at the physiological significance of spatial information coding in neuronal regulatory RNAs. PUBLIC HEALTH RELEVANCE: Spatial information coding in neuronal npcRNAs, it is hypothesized, is a key prerequisite for local translational control mechanisms that are underlying long-term synaptic plasticity. The planned research is directed at mechanism and modulation of targeted npcRNA delivery to synapto-dendritic destination sites. A molecular understanding of spatial RNA coding in neurons will enable us to appreciate its relevance in neuronal plasticity, drug action, and human disease.