Molecular determinants of the axonal mRNA transcriptome

Abstract

Axonal protein synthesis has been shown to play a role in developmental and regenerative growth, as well as in cell body responses to axotomy. Recent studies have begun to identify the protein products that contribute to these autonomous responses of axons. In the peripheral nervous system, intra-axonal protein synthesis has been implicated in the localized in vivo responses to neuropathic stimuli, and there is emerging evidence for protein synthesis in CNS axons in vivo. Despite that hundreds of mRNAs have now been shown to localize into the axonal compartment, knowledge of what RNA binding proteins are responsible for this is quite limited. Here, we review the current state of knowledge of RNA transport mechanisms, and highlight recently uncovered mechanisms for dynamically altering the axonal transcriptome. Both changes in the levels or activities of components of the RNA transport apparatus and alterations in transcription of transported mRNAs can effectively shift the axonal mRNA population. Consistent with this, the axonal RNA population shifts with development, with changes in growth state, and in response to extracellular stimulation. Each of these events must impact the transcriptional and transport apparatuses of the neuron, thus directly and indirectly modifying the axonal transcriptome.

IMP2 axonal localization, RNA interactome, and function in the development of axon trajectories

“…IMP1 immunolabeling appeared ubiquitous in spinal cord (Fig. 1D,E), consistent with many previous studies showing that IMP1 has widespread roles in neurons and other cell types (Kiebler and Bassell, 2006;Rodriguez et al, 2008;Gomes et al, 2014). IMP3 (Igf2bp3), the family member most closely related to IMP1 in sequence, showed broad labeling comparable to IMP1 (Fig.…”

“…However, only a few specific RNA-binding proteins have been studied in the context of neuron and axon development, and more generally the biological functions of most RNA-binding proteins remain little characterized (Hornberg and Holt, 2013). Among the best-studied is IMP1 (also known as Igf2bp1 or ZBP1), which binds to the 'zipcode' sequence in the 3′UTR of β-actin mRNA, and regulates β-actin mRNA transport and local translation in fibroblasts, neurons and other cell types (Kiebler and Bassell, 2006;Rodriguez et al, 2008;Gomes et al, 2014). A related member of the IMP family is IMP2 (also known as Igf2bp2), but its function is not well characterized and has only recently begun to emerge.…”

hnRNPs Interacting with mRNA Localization Motifs Define AxoNAl RNA Regulons

“…RNA binding proteins (RBPs) interacting with structural motifs within these mRNAs drive these posttranscriptional mechanisms (5). For example, zip-code binding protein 1 (ZBP1, also called IGF-II mRNA binding [IMP1]) protein was shown to bind to a 56 nucleotide (nt) stem-loop structure in the 3' untranslated region (UTR) of β-actin mRNA (Actb), and this binding is necessary for axonal transport of the mRNA (6,7).…”

RNA Structures as Mediators of Neurological Diseases and as Drug Targets

“…Secondary structure elements in introns of mRNAs and in 5′ and 3′ UTRs have been identified as important markers for cellular splicing machinery (Buratti and Baralle, 2004), mRNA trafficking (e.g., axonal and dendritic transport (Gomes et al, 2014; Jung et al, 2012)), and translation initiation (Hughes, 2006). Stem-loops that contain canonical nucleotide sequences in their apical loop are markers for NOVA-1 recruiting.…”