Function and regulation of local axonal translation

Abstract

An increasing body of evidence indicates that local axonal translation is required for growing axons to respond appropriately to guidance cues and other stimuli. Recent studies suggest that asymmetrical synthesis of cytoskeletal proteins mediates growth cone turning and that local translation and retrograde transport of transcription factors mediate neuronal survival. Axonal translation is regulated partly by selective axonal localization of mRNAs and by translation initiation factors and RNA-binding proteins. We discuss possible rationales for local axonal translation, including distinct properties of nascent proteins, precise localization, and axonal autonomy.

Figure 1

The ‘differential translation’ model for local translation in growth cones. (a) A gradient of attractive guidance cue, such as netrin-1, induces asymmetrical activation of translation and transport of mRNAs, causing asymmetrical translation of proteins that build up the cytoskeleton, which leads to attractive turning. (b) A gradient of repulsive guidance cue, such as Slit-2, induces similar asymmetrical activation of translation but induces transport and translation of different mRNAs, causing asymmetrical translation of proteins that disassemble the cytoskeleton, which leads to repulsive turning.

Figure 2

Local translation and communication between the axon and cell body. (1) Stimulation of axons leads to transcription-independent differential localization of mRNAs to the axon through transport on microtubules, changing the population of mRNAs available for local axonal translation. (2) Newly synthesized transcription factors can be retrogradely transported on microtubules to the cell body where they influence transcription.

Figure 3

Correlation analysis of mRNA localization data from [44^••] indicates clustering of axonal mRNA trafficking responses to related stimuli. In this network graph, correlations between responses to each stimulus are represented as distances (high correlation = short distance). The fold changes (x) in the axonal localization of 51 mRNAs in response to extracellular stimuli were taken from [44^••] and converted to a linear scale y according to y = x – |x|/x. For each pair of stimuli, the Pearson correlation coefficient r was calculated for y across the 51 genes. The five stimulation conditions were drawn as points where each pair of stimuli is connected by a line of length of approximately 1 – r, using Graphviz software, with values of significant correlations shown. Line lengths are not exact because of geometrical constraints. Lines representing correlations that are not statistically significant (p > 0.05) are shaded gray.