Regrowth of an axon after injury is an inherently metabolic undertaking. Yet the mechanisms of metabolic regulation that influence repair following injury are not well understood. O-linked β-N-acetylglucosamine (O-GlcNAc) is a post-translational modification of serines and threonines that functions as a sensor of cellular nutrients. Performing in vivo laser axotomies in Caenorhabditis elegans, we find that neuronal regeneration is substantially increased by disruptions of either the O-GlcNAc transferase or the O-GlcNAcase that decrease and increase O-GlcNAc levels, respectively. A lack of O-GlcNAc induces the AKT-1 branch in the insulin-signaling pathway to use glycolysis. In contrast, increased O-GlcNAc levels activate an opposing branch of the insulin-signaling pathway whereby SGK-1 modulates the FOXO transcription factor DAF-16 to influence mitochondrial function. The existence of this toggle-like mechanism between metabolic pathways suggests that O-GlcNAc signaling conveys cellular nutrient status to orchestrate metabolism in a damaged neuron and maximize the regenerative response.
Keywords: C.elegans; O-GlcNAc; axon regeneration; insulin-signaling; neuronal metabolism.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.