Molecular control of local translation in axon development and maintenance

Abstract

The tips of axons are often far away from the cell soma where most proteins are synthesized. Recent work has revealed that axonal mRNA transport and localised translation are key regulatory mechanisms that allow these distant outposts of the cell to respond rapidly to extrinsic factors and maintain axonal homeostasis. Here, we review recent evidence pointing to an increasingly broad role for local protein synthesis in controlling axon shape, synaptogenesis and axon survival by regulating diverse cellular processes such as vesicle trafficking, cytoskeletal remodelling and mitochondrial integrity. We further highlight current research on the regulatory mechanisms that coordinate the localization and translation of functionally linked mRNAs in axons.

Axonal precursor mi RNA s hitchhike on endosomes and locally regulate the development of neural circuits

“…A widely accepted view posits that local translation in axons is triggered by stimuli, by either chemotropic and maturation cues during development or under injury conditions in adults (Cioni et al , ). For instance, Sema3A induces the synthesis of proteins that elicit cytoskeletal remodeling and steering (Campbell et al , ; Wu et al , ).…”

FMRP binding to a ranked subset of long genes is revealed by coupled CLIP and TRAP in specific neuronal cell types

“…Finally the local translation of these long synaptic proteins encoding cell adhesion molecules, scaffolding proteins, channels and receptors may be responsible for changes in synaptic strength following synaptic activity as the synapses grow on both the pre-and post-synaptic sides during development and due to experience. Once localized to the synapse these mRNAs are likely maintained in a translationally repressed state during the stage of elongation until suitable synaptic signals release this repression [241][242][243][244][245][246][247][248] . This has been suggested to be a common mechanism regulating protein synthesis in neuronal processes 35,[249][250][251] .…”

The role of 3’UTR-protein complexes in the regulation of protein multifunctionality and subcellular localization

“…Nevertheless, this study provides for the first time an extensive overview of the 3'UTR-protein complex formation for a subset of human proteins, predicting that a sizeable amount of such cellular complexes can be formed, employing a large variety of RBPs and intermediate protein components.The diversity in subcellular localization and protein partners are two main protein multifunctionality determinants possibly influenced and driven by 3'UTRs. 3'UTRs are generally described as responsible for the localization of their cognate mRNAs in asymmetrical and polarized cells such as neurons, where localized translation modifies the nearby proteome in response to external cues12,45 . This is mediated by RBPs that interact with motor proteins, allowing the transport of mRNA along actin cables.…”