RNA-based control of wiring the brain

Axon guidance is a key step in wiring the brain. To establish neural circuits, the axons of differentiating neurons must navigate accurately to distant targets and select precise synaptic partners. We are trying to understand the mechanisms that underlie these highly selective processes in the vertebrate visual system. Emerging evidence points to an increasingly important role for post-transcriptional mechanisms such as RNA localization and local protein synthesis. Sub-cellular profiling shows that axonal growth cones contain a remarkably diverse repertoire of mRNAs that are dynamically regulated with age. In vitro functional assays reveal that directional turning responses of growth cones to some guidance cues depend on local protein synthesis. Our studies support a ‘differential translation model' for axon steering in which attractive and repulsive cues induce opposite turning behaviours through eliciting translation of distinct mRNAs. An important component of this cue-induced translation is that it can be controlled with high spatial precision enabling localized sub-cellular responses. A polarised cue, for example, triggers protein synthesis on the near-stimulus side of the 5 micron growth cone that is achieved through co-ordinately regulated asymmetries in receptor activation, mRNA trafficking and translation activation. RNA-binding protein studies are beginning to provide in vivo evidence that RNA-based mechanisms play a pre-synaptic role in establishing synaptic connections in the visual system.