Local translation and directional steering in axons

Abstract

The assembly of functional neural circuits in the developing brain requires neurons to extend axons to the correct targets. This in turn requires the navigating tips of axons to respond appropriately to guidance cues present along the axonal pathway, despite being cellular 'outposts' far from the soma. Work over the past few years has demonstrated a critical role for local translation within the axon in this process in vitro, making axon guidance another process that requires spatially localized translation, among others such as synaptic plasticity, cell migration, and cell polarity. This article reviews recent findings in local axonal translation and discusses how new protein synthesis may function in growth cone guidance, with a comparative view toward models of local translation in other systems.

Figure 1

Hypothesis for cue-induced asymmetrical synthesis of cytoskeletal proteins. A guidance cue gradient causes an asymmetrical activation of translation initiation, ‘opening the gates' to translation asymmetrically. mRNAs are selected for translation according to whether the guidance cue is attractive or repulsive, which may also depend on the internal state of the growth cone. For an attractive guidance cue, proteins that promote actin assembly are asymmetrically synthesized (green dots), whereas for a repulsive guidance cue, proteins that promote actin disassembly (red dots) are asymmetrically synthesized.

Figure 2

A model for regulation of translation in axonal growth cones. Guidance cues induce global activation of cap-dependent translation by activating translation initiation factors (left, ‘global activation of translation'). This activation is largely ‘permissive,' as translation of most mRNAs is also controlled by RNA-binding proteins and possibly microRNAs. By regulating these factors, different guidance cues—modulated by the internal state of the growth cone (e.g., cAMP levels)—can cause different effects by activating the translation of different mRNAs (right, ‘mRNA-specific regulation'). Translation is also regulated by the differential transport of specific mRNAs to the growth cone, which is also controlled by RNA-binding proteins (bottom, ‘mRNA-specific transport'). Dotted lines indicate hypothetical connections.

Figure 3

Comparison of models of stimulus-induced local translation in axon guidance, cell migration, and synaptic plasticity. mRNAs are transported to and within the growth cone (A), to the leading edge of migrating cells (B), and into dendrites and dendritic spines (C). Impinging signals stimulate translation of specific mRNAs, resulting in the formation of new proteins (green dots) in the appropriate location, thus changing the morphology or function of a localized subcellular compartment. Note that local translation occurs on a similar spatial scale across these systems, in subcellular compartments of the order of microns.