Crerar, Hamish; (2018) The axonal transcript Tp53inp2 mediates the development of the sympathetic nervous system. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Nerve Growth Factor (NGF) is a neurotrophin essential for the survival of sympathetic and sensory neurons. Localisation of mRNA in axons of NGF- dependent neurons supports growth and maintains axon integrity, however how localised transcripts regulates most axonal functions remains unknown. To characterise the 3’UTR of transcripts localised in sympathetic neuron axons, we performed a 3’end RNA-Seq on mRNA isolated from either axons or cell bodies of neurons cultured in compartmentalised chambers. We identified Tp53inp2 as the most abundant transcripts in axons, accounting for almost one third of the reads. Interestingly, despite the abundance of its RNA, the protein for Tp53inp2 is not detectable within axons of sympathetic neurons. We observe that Tp53inp2 is not actively translated, held in a strictly repressed state mediated by its UTRs. Deletion of Tp53inp2 in sympathetic neurons in vivo and in vitro affects both cell survival and axon growth, suggesting a critical role for Tp53inp2 in neuronal development, despite the lack of translation. That this phenotype can be rescued by transfecting a non- translatable form of the transcript, suggests that instead Tp53inp2 acts as an atypical non-coding RNA, whose function is mediated through interaction with the NGF receptor TrkA. We conclude that Tp53inp2 mRNA regulates sympathetic neuron survival and axon growth in a coding-independent manner by interacting with TrkA receptor and enhancing axonal NGF- dependent signalling.

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