In neurons, local protein synthesis is an important instrument in the modulation of synaptic strength. The specificity of this mechanism is determined, at least in part, by the identity of mRNAs that are locally available for on-site translation. The targeted delivery of select RNAs to synapto-dendritic domains is therefore a key underpinning of neuronal function and plasticity. For this reason, it is essential that we understand molecular information coding mechanisms that specify and implement dendritic targeting of neuronal RNAs. Our understanding of dendritic RNA targeting mechanisms has remained rudimentary, despite progress in recent years. At a most fundamental level, we need to identify and comprehend the codes that are used by RNAs to specify synapto-dendritic delivery. We need to decipher conditional codes, i.e. those contained in RNA targeting elements that specify inducible targeting. We need to gain insight into mechanisms that targeting factors use to decode such elements and initiate targeting in an activity-dependent manner. To address these critical issues in neuronal cell biology, the proposed project will conduct a functional dissection of the molecular and cellular basis of dendritic RNA targeting mechanisms. The planned research will be directed at the overarching hypothesis that noncanonical RNA motifs serve as dendritic targeting code determinants. Specifically, Aim 1 will address the question whether noncanonical targeting motif subtypes carry discrete spatial codes that are determinants of conditional vs. constitutive dendritic RNA transport.
Aim 2 will test the hypothesis that motif codes are recognized by cognate dendritic targeting factors, and that differential recognition specifies conditional vs. constitutive transport.
Aim 3 will establish whether conditional dendritic RNA targeting mediated by such motifs is inducible by neuronal activity and receptor activation. It will be the long-term goal of the planned project to arrive ata molecular understanding of neuronal mechanisms that mediate activity-dependent RNA transport in dendrites.
Impaired RNA transport mechanisms are increasingly linked to disease. Dysregulated RNA transport in neurons has been implicated in disorders such as Alzheimer's disease (AD) and the fragile X associated tremor/ataxia syndrome (FXTAS). Our work is directed at the molecular and cellular basis of neuronal RNA transport mechanisms, and we trust that in-depth insights into such mechanisms will subsequently enable us to recognize defects that lead to disease.
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