Walking the line: mechanisms underlying directional mRNA transport and localisation in neurons and beyond

Abstract

Messenger RNA (mRNA) localisation enables a high degree of spatiotemporal control on protein synthesis, which contributes to establishing the asymmetric protein distribution required to set up and maintain cellular polarity. As such, a tight control of mRNA localisation is essential for many biological processes during development and in adulthood, such as body axes determination in Drosophila melanogaster and synaptic plasticity in neurons. The mechanisms controlling how mRNAs are localised, including diffusion and entrapment, local degradation and directed active transport, are largely conserved across evolution and have been under investigation for decades in different biological models. In this review, we will discuss the standing of the field regarding directional mRNA transport in light of the recent discovery that RNA can hitchhike on cytoplasmic organelles, such as endolysosomes, and the impact of these transport modalities on our understanding of neuronal function during development, adulthood and in neurodegeneration.

Keywords: Axonal transport; Neurodegeneration; Vesicular traffic.

Fig. 1

Summary of direct motor-mRNA granule interactions for mRNA transport across different systems. a Proteins involved in ASH1 mRNA transport along actin filaments into the newly formed bud in budding yeast. Additional RBPs still to be identified are marked by a question mark. b-i Diagram of a stage 10/12 Drosophila oocyte, showing the Egl-BicD complex mediating the transport of bicoid, gurken and oscar mRNAs from nurse cells into the forming oocyte during oogenesis. Oskar mRNA is initially released into the oocyte and is later transported in a complex with kinesin-1 and Stau1 and possibly other still unidentified RBPs to the posterior pole (b-ii). c Schematic summarising the main motor proteins and RBPs mediating mRNA transport in dendrites and axons (c-i) and potentially in pre- and post-synaptic regions (c-ii). The adaptor identity in (c-i) is currently unknown, in vitro reconstitution studies suggest KAP3 to be one potential adaptor [96]. Question marks indicate that the stoichiometry and exact composition of these complexes are still unclear. Furthermore, whether myosin Va drives the transport of mRNPs is still under investigation. Ribosomal proteins have also been observed in mRNA transport granules in neurons, but have been omitted for clarity. See main text for further information

Fig. 2

Organelle hitchhiking as a mechanism of mRNA granule transport. a Schematic showing the machinery involved in the transport of cdc3 mRNA in U. maydis. All four septin mRNAs and the corresponding proteins have also been shown to localise to shuttling endosomes, but they have been omitted for clarity. Pab1 stands for poly-A binding protein. Diagram of RNA granule is adapted from [116]. b Endosomal/lysosomal hitchhiking in neurons. ANXA11 acts as a tether between RNA granules and LAMP1-positive organelles by exploiting a phase-separation mechanism only partially understood. G3BP1 is one of the components of these transported RNA granules. See main text for additional details