Dynamics of axonal mRNA transport and implications for peripheral nerve regeneration

Abstract

Locally generating new proteins in subcellular regions provides means to spatially and temporally modify protein content in polarized cells. Recent years have seen resurgence of the concept that axonal processes of neurons can locally synthesize proteins. Experiments from a number of groups have now shown that axonal protein synthesis helps to initiate growth, provides a means to respond to guidance cues, and generates retrograde signaling complexes. Additionally, there is increasing evidence that locally synthesized proteins provide functions beyond injury responses and growth in the mature peripheral nervous system. A key regulatory event in this translational regulation is moving the mRNA templates into the axonal compartment. Transport of mRNAs into axons is a highly regulated and specific process that requires interaction of RNA binding proteins with specific cis-elements or structures within the mRNAs. mRNAs are transported in ribonucleoprotein particles that interact with microtubule motor proteins for long-range axonal transport and likely use microfilaments for short-range movement in the axons. The mature axon is able to recruit mRNAs into translation with injury and possibly other stimuli suggesting that mRNAs can be stored in a dormant state in the distal axon until needed. Axotomy triggers a shift in the populations of mRNAs localized to axons indicating a dynamic regulation of the specificity of the axonal transport machinery. In this review, we discuss how axonal mRNA transport and localization are regulated to achieve specific changes in axonal RNA content in response to axonal stimuli.

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

“…The formation of a new growth cone after axotomy of developing axons in vitro requires both local protein synthesis and degradation [30], and upon injury of mature axons, mRNAs and protein synthesis machinery are rapidly recruited into axons and intraaxonal translation is upregulated or re-activated within these mature axons [31][32][33][34]. Locally synthesized proteins are required for communication from the injured axons to their soma and likely participate in the formation of the growth bulb at the site of injury [35,36]. Several recent excellent reviews have been published covering the multifaceted role of local translation in injured axons [37][38][39]; here, we will focus on the question whether manipulation of the local translatome in injured axons might be of therapeutic value.…”

MicroRNA-132 Is Enriched in Developing Axons, Locally Regulates Rasa1 mRNA, and Promotes Axon Extension

“…Developing axons contain protein synthesis machinery and a specific set of mRNAs, and roles for local axonal mRNA translation have been described in axon growth, guidance, and regeneration (Hengst and Jaffrey, 2007;Yoo et al, 2010;Jung et al, 2012). However, the mechanisms that regulate axonal mRNA translation are still not well understood.…”

Peripheral nerve graft with immunosuppression modifies gene expression in axotomized CNS neurons

“…The lower expression of Mmps and Timp3 may indicate a protective effect of the graft on the injured neurons. The relatively low expression of cytoskeletal genes in the I-PNG neurons is puzzling; we suggest that synthesis of proteins associated with axonal regeneration into the PNG occurs through local synthesis in the axon and is stimulated by injury (Willis et al, 2007;Taylor et al, 2009;Yoo et al, 2010). Among those synthesized in axons and that were identified by our analysis include b-Actin (Bassell et al, 1998), Creb (Cox et al, 2008), Gap43 (Willis et al, 2005(Willis et al, , 2007, Map1b (Antar et al, 2006), Peripherin (Willis et al, 2005(Willis et al, , 2007, and Tubb3 (Gumy et al, 2011;Willis et al, 2005Willis et al, , 2007.…”