ABSTRACT Our understanding of the intrinsic mechanisms that drive the regeneration of damaged axons after a spinal cord injury is still limited. Microtubules are core components of the eukaryotic cytoskeleton and are essential for axonal growth, in part because their stability is governed by post‐translational modifications in mature neurons. Glucose‐dependent insulinotropic polypeptide (GIP) and its receptor (GIPR) are expressed in multiple extra‐pancreatic tissues, suggesting biological functions beyond classical endocrine signaling; however, their roles in neuronal cytoskeletal regulation are not well defined. Here, we investigated the effects of GIP in cultured cortical neurons. GIP enhanced microtubule stability and increased the number of axons crossing an inhibitory chondroitin sulfate proteoglycan (CSPG) border. Mechanistically, GIP promoted microtubule acetylation via α‐tubulin N‐acetyltransferase 1 (αTAT1), the major acetyltransferase for α‐tubulin, by suppressing αTAT1 ubiquitination and thereby reducing its proteasomal degradation in inhibitory environments. Although the upstream mechanism remains to be determined, this study provides the first evidence that GIP/GIPR signaling modulates microtubule dynamics, highlighting a potential strategy to re‐activate neuronal growth machinery after injury.
Guo et al. (Tue,) studied this question.