2018 Theses Doctoral

Regulation of Neuronal mRNA Localization by Exclusion

Martinez, Jose Carlos

Intra-axonal protein synthesis is important for the proper wiring of the nervous system and can have restorative or pathogenic effects in response to nerve injury and neurodegenerative stimuli. The set of axonally translated transcripts, the axonal translatome, is regulated through the control of mRNA localization, stability, and translation. Targeting the axonal translatome could result in the development of novel therapies for the treatment of neurological disorders. Yet, there are gaps in our understanding of the selective mechanism regulating the specific localization of mRNAs into axons. Currently, axonal localization of transcripts is understood to be controlled by the presence of sequence elements that direct axonal transport. In an attempt to identify novel localization motifs, I found that a well-known motif corresponding to the Pumilio Binding Element (PBE) is significantly depleted in axonally enriched mRNAs. Moreover, I found this element to be highly informative of axonal mRNA localization and translation across different neuronal types and developmental stages suggesting that it is a highly conserved regulatory motif. I found Pum2 neuronal expression and subcellular localization to be highly consistent with the way the PBE predicts mRNA regulation. I then demonstrated that interfering with Pum2 function results in increased axonal localization of PBE containing mRNAs. Finally, Pum2 downregulation was associated with gross defects in axonal outgrowth, branching, and regeneration. Altogether, this data suggests that Pum2 regulates axonal mRNA localization through an exclusion mechanism that is important during neuronal development.