TEMPORAL REGULATION OF LOCALIZED MRNA TRANSLATION IN REGENERATING AXONS

Nemours Children'S Hospital, Delaware, Wilmington DE

Investigators

Linked publications & trials

Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Localized translation of mRNAs plays a role in axonal pathfinding, injury signaling and regeneration. The capacity for axonal protein synthesis has further been shown to correlate with the capacity for axonal regeneration. Localization of mRNAs is most often controlled by elements, most often found within the 3'untranslated regions (UTRs) of the transcripts that are bound by RNA targeting/transport machinery as we recently showed for RanBP1 mRNA. Once localized to a subcellular region, neuronal mRNAs are also subjected to translational control and this can be highly specific for individual mRNAs. However, we have little knowledge of the intracellular pathways that underlay this translational control and we do not know how the axon chooses which mRNAs to translate in response to any given stimulus. This proposal focuses on these two issues. I hypothesize that cation-signaling mechanisms converge on the translational apparatus in axons to confer temporal specificity to protein synthesis. In the first aim, I will focus on which mRNA elements confer translational specificity. In the second aim, I will isolate the RNA binding proteins that bind to the cis-elements of these mRNAs and characterize the mechanism of translational regulation in axon. In the third aim, I will determine whether Ca2+ directly or indirectly regulates translation in the axonal compartment. Together, these studies will provide a unique view of translational specificity in axons and lay the foundation for future therapeutic neural repair strategies aimed at modulating localized protein synthesis.