Abstract
In a number of animal species, the growth-associated protein (GAP), GAP-43 (aka: F1, neuromodulin, B-50, G50, pp46), has been implicated in the regulation of presynaptic vesicular function and axonal growth and plasticity via its own biochemical properties and interactions with a number of other presynaptic proteins. Changes in the expression of GAP-43 mRNA or distribution of the protein coincide with axonal outgrowth as a consequence of neuronal damage and presynaptic rearrangement that would occur following instances of elevated patterned neural activity including memory formation and development. While functional enhancement in GAP-43 mRNA and/or protein activity has historically been hypothesized as a central mediator of axonal neuroplastic and regenerative responses in the central nervous system, it does not appear to be the crucial substrate sufficient for driving these responses. This review explores the historical discovery of GAP-43 (and associated monikers), its transcriptional, post-transcriptional and post-translational regulation and current understanding of protein interactions and regulation with respect to its role in axonal function. While GAP-43 itself appears to have moved from a pivotal to a supporting factor, there is no doubt that investigations into its functions have provided a clearer understanding of the biochemical underpinnings of axonal plasticity.
Highlights
SummaryFive independent lines of research came to complementary and overlapping conclusions on the fundamental properties of an axonal-associated membrane-bound protein related to axonal plasticity
The historical and current work investigating the role of GAP-43 in nervous system function has revealed that its mRNA expression or protein levels increase in conjunction with axonal structural plasticity as occur during development and maturation, with input-dependent memory related processes and following axonal injury during the regeneration phase
Because all of these events can culminate in reorganization of presynaptic elements, the transcriptional and post-transcriptional regulation of the mRNA and the post-translational modification and protein localization were intensely scrutinized as a means to facilitate central nervous system plasticity
Summary
Five independent lines of research came to complementary and overlapping conclusions on the fundamental properties of an axonal-associated membrane-bound protein related to axonal plasticity. While the author of this review concludes that the transcriptional, post-transcription and post-translational regulation of numerous proteins coordinates axonal plasticity, the work that explored the contribution of GAP-43 to axonal outgrowth has been instrumental in elucidating basic mechanisms of axonal growth and function. Since those reports, interest in GAP-43 (the nomenclature for this protein used in the current review) rose sharply peaking at 134 PubMed reports in 1995 but showing a decreasing trend over the past 20 years (lowest in 2016 at 65 publications). A review of the transcriptional and translational aspects of GAP-43 as they pertain to the moderation of neuroplastic events in the central nervous system will be examined in relation to the function of this protein as an important node in axonal outgrowth during development and regeneration following injury
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