Zimmermann, C; (2013) Regulation of mRNA localization, stability and local translation in sympathetic neuron axons. Doctoral thesis , UCL (University College London).

Abstract

Polarity is dependent on the asymmetric distribution of proteins, which can be especially challenging in neurons as the nucleus, where transcription takes place, can be far away from the final location of the protein. One essential mechanism by which protein compartmentalization can be achieved is through the targeting of specific mRNA transcripts to specific cellular regions where they are locally translated. Neurotrophin 3 (NT3) is secreted by blood vessels and is required for the initial growth of proximal sympathetic neuron axons along the vasculature. NGF on the other hand, is secreted by the sympathetic target tissue and is required for sympathetic neuron survival and the final innervation of target organs. Although both neurotrophins act through the common receptor TrkA, NGF supports TrkA internalisation and retrograde signalling from distal axons to cell bodies to regulate gene expression, whereas NT3 can only induce a local signalling response in axons and is unable to support retrograde TrkA signalling. I performed a Digital Gene Expression Tag Profiling of axonal and cell body mRNA obtained from rat superior cervical ganglia cells maintained with NT3 with the aim of identifying mRNAs localized in subcellular compartments and to understand the control of mRNA stability and local protein translation in axons. I found that several hundred transcripts are significantly enriched in axons of sympathetic neurons when compared to cell bodies. Rapid Amplification of cDNA Ends (RACE) analysis of untranslated regions (UTRs) of candidate genes showed that at least some of the transcripts enriched in axons possess different UTRs. The most abundant transcript in axons was SCG10 (or Stmn2), a regulator of microtubule dynamics. Furthermore, I identified a member of the Hu protein family as an RNA binding protein that interacts with the UTR of SCG10 and will discuss its potential role in neurotrophin-dependent regulation of SCG10 mRNA stability and translation.

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