Molecular determinants of axonal RNA translation

Nemours Children'S Hospital, Delaware, Wilmington DE

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Abstract

Localization of mRNAs with subsequent translation into new proteins provides a means to geographically regulate neuronal protein composition in distinct subcellular regions. In axons, this localized protein synthesis is needed for growth cone guidance and regeneration. Although mature axons show little evidence for localized protein synthesis, injury appears to increase the neuron's ability to locally generate new axonal proteins. We suspect that injury invokes a fundamental change in how the neuron targets mRNAs into and translates mRNAs within axons. Locally synthesizing proteins at sites distal from the neuronal perikaryon requires a coordinated effort to package and target mRNAs and translational machinery for delivery to the correct locale. In large part, this targeting is accomplished through specific RNA-protein interactions. For axonal mRNA transport and translation, exceptionally little is known of which mRNA elements are needed for this RNA-protein interaction and which RNA binding proteins are targeted into axons. Here we propose to dissect the molecular determinants for targeting mRNAs into axons. In the first aim, we will determine the localizing elements of axonal mRNAs that are regulated at the level of transport, translation, or both using PNS sensory neurons. In the second aim, we will test functionality of these RNA localization elements in CNS neurons that show complete axonal-dendritic polarization. Finally, we will generate and characterize viral reporter constructs that will enable us to address RNA localization mechanisms in vivo.