Regulation of Neuronal Gene Expression by Local Axonal Translation

Abstract

RNA localization is a key mechanism in the regulation of protein expression. In neurons, this includes the axonal transport of select mRNAs based on the recognition of axonal localization motifs in these RNAs by RNA binding proteins. Bioinformatic analyses of axonal RNAs suggest that selective inclusion of such localization motifs in mature mRNAs is one mechanism controlling the composition of the axonal transcriptome. The subsequent translation of axonal transcripts in response to specific stimuli provides precise spatiotemporal control of the axonal proteome. This axonal translation supports local phenomena including axon pathfinding, mitochondrial function, and synapse-specific plasticity. Axonal protein synthesis also provides transport machinery and signals for retrograde trafficking to the cell body to effect somatic changes including altering the transcriptional program. Here we review the remarkable progress made in recent years to identify and characterize these phenomena.

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

“…Because neurons are so highly polarized, transport of mRNAs along the axon and dendrites to undergo local, on-site protein synthesis is key for maintaining proper structural and functional polarity (Bramham, 2008;Cioni et al, 2018;Rangaraju et al, 2017;Tom Dieck et al, 2014). In these subcompartments, FMRP and its homologs, the fragile X-related proteins FXR1P and FXR2P, assemble with other RNA-binding proteins and coding and noncoding RNAs to form large ribonucleoprotein particles or granules that tightly regulate mRNA transport, translation, stability, and degradation (Akins et al, 2012;Korsak et al, 2016;Bagni, 2014a, 2014b). In axons and dendrites, fragile X granules are transported along microtubules in a translationallyquiescent manner through interactions with kinesin, myosin, and dynein motor proteins (Kanai et al, 2004).…”

Axonal ribosomes and mRNAs associate with fragile X granules in adult rodent and human brains

“…One conceptually attractive solution to this challenge is the local translation of mRNAs in the axon. Translation in developing and regenerating axons is well documented (2,3), and recent evidence suggests that CNS axons in the mammalian brain may also utilize this mechanism (4,5). However the extent to which endogenous ribosomes, mRNA and translational regulators localize to adult brain axons that are integrated into mature circuitry is unknown (6,7).…”

The FXR2P low complexity domain drives assembly of multiple fibril types with differing ribosome association in neurons

“…One important mechanism for such spatiotemporal control is local protein synthesis where mRNAs are targeted to specific domains and can be rapidly translated in response to nearby cues. This process has long been appreciated in dendrites (Holt and Schuman 2013;; Sutton and Schuman 2006) and recent evidence indicates that analogous translational machinery is also present in axons (Zheng et al, 2001;; Christie et al, 2009;; Taylor et al, 2009;; Korsak et al, 2016;; Shigeoka et al, 2016;; Akins et al, 2017;; Batista et al, 2017). Local protein synthesis is in part controlled by RNA binding proteins (RBPs) that can influence transcript fate through regulation of RNA biogenesis, localization, translation and degradation (Kapeli & Yeo, 2012;; Darnell, 2013;; Calabretta and Richard, 2015).…”