Regulation of NGF Signaling by an Axonal Untranslated mRNA

Hamish Crerar,Emily Scott-Solomon,Chantal Bodkin-Clarke,Catia Andreassi,Maria Hazbon,Emilie Logie,Marifé Cano-Jaimez,Marco Gaspari,Rejji Kuruvilla,Antonella Riccio

doi:10.1016/j.neuron.2019.02.011

Abstract

SummaryNeurons are extraordinarily large and highly polarized cells that require rapid and efficient communication between cell bodies and axons over long distances. In peripheral neurons, transcripts are transported along axons to growth cones, where they are rapidly translated in response to extrinsic signals. While studying Tp53inp2, a transcript highly expressed and enriched in sympathetic neuron axons, we unexpectedly discovered that Tp53inp2 is not translated. Instead, the transcript supports axon growth in a coding-independent manner. Increasing evidence indicates that mRNAs may function independently of their coding capacity; for example, acting as a scaffold for functionally related proteins. The Tp53inp2 transcript interacts with the nerve growth factor (NGF) receptor TrkA, regulating TrkA endocytosis and signaling. Deletion of Tp53inp2 inhibits axon growth in vivo, and the defects are rescued by a non-translatable form of the transcript. Tp53inp2 is an atypical mRNA that regulates axon growth by enhancing NGF-TrkA signaling in a translation-independent manner.

Highlights

Neurons are highly morphologically complex cells that require the expression of a large number of genes encoding proteins that support growth, branching and synaptic functions in dendrites, and growth cone migration, extension, and regeneration in axons (Andreassi et al, 2018; Terenzio et al, 2017)
Transcripts are transported to dendrites and axons, where they can be rapidly translated in response to extrinsic signals, such as synaptic activity, neurotrophic factors, guidance cues, and injury
To obtain a comprehensive characterization of the 30 UTR transcript isoforms expressed in sympathetic neuron axons, we performed 30 end RNA sequencing (RNA-seq) on mRNA isolated from either axons or cell bodies of rat sympathetic neurons cultured in compartmentalized chambers (Andreassi et al, 2019)

Summary

Graphical Abstract

Crerar et al report that Tp53inp, an mRNA transcript abundantly localized in axons of sympathetic neurons, interacts with the NGF receptor TrkA. The Tp53inp transcript is not translated but acts in a coding-independent manner to regulate axon growth and neuronal survival in vivo. Highlights d Tp53inp is the most abundant mRNA in SN axons but is not translated d Tp53inp transcript interacts with the TrkA receptor to regulate NGF signaling d In SNs, Tp53inp functions independently of its proteincoding capacity d Tp53inp transcript is essential for axon growth and target innervation in vivo. 2019, Neuron 102, 553–563 May 8, 2019 a 2019 The Authors.

SUMMARY

INTRODUCTION

Findings

METHOD DETAILS