Microtubules are a major cytoskeletal component of neurites, and the regulation of microtubule stability is essential for neurite morphogenesis. βPix (ARHGEF7) is a guanine nucleotide exchange factor for the small GTPases Rac1 and Cdc42, which modulate the organization of actin filaments and microtubules. βPix is expressed as alternatively spliced variants, including the ubiquitous isoform βPix-a and the neuronal isoforms βPix-b and βPixd, but the function of the neuronal isoforms remains unclear. Here, we reveal the novel role of βPix neuronal isoforms in regulating tubulin acetylation and neurite outgrowth. At DIV4, hippocampal neurons cultured from βPix neuronal isoform knockout (βPix-NIKO) mice exhibit defects in neurite morphology and tubulin acetylation, a type of tubulin modification which often labels stable microtubules. Treating βPix-NIKO neurons with paclitaxel, which stabilizes the microtubules, or reintroducing either neuronal βPix isoform to the KO neurons overcomes the impairment in neurite morphology and tubulin acetylation, suggesting that neuronal βPix isoforms may promote microtubule stabilization during neurite development.βPix-NIKO neurons also exhibit lower phosphorylation levels for Stathmin1, a microtubuledestabilizing protein, at Ser16. Expressing either βPix neuronal isoform in the βPix-NIKO neurons restores Stathmin1 phosphorylation levels, with βPix-d having a greater effect than βPix-b. Furthermore, we find that the recovery of neurite length and Stathmin1 phosphorylation via βPix-d expression requires PAK kinase activity. Taken together, our study demonstrates that βPix-d regulates the phosphorylation of Stathmin1 in a PAK-dependent manner and that neuronal βPix isoforms promote tubulin acetylation and neurite morphogenesis during neuronal development. OPEN ACCESS Citation: Kwon Y, Jeon YW, Kwon M, Cho Y, Park D, Shin JE (2020) βPix-d promotes tubulin acetylation and neurite outgrowth through a PAK/ Stathmin1 signaling pathway. PLoS ONE 15(4): e0230814. https://doi.org/10.]. Microtubules are major components of the cytoskeleton in dendritic and axonal shafts [2]. Post-translational modifications of the microtubules vary in different regions of a neuron and change during neuronal morphogenesis. Those modifications affect the dynamics and stability of the microtubules that contribute to neuronal morphogenesis [3,4]. The deregulation of microtubule dynamics via genetic or pharmacological manipulation of the tubulin post-translational modifications often leads to defective neurite morphogenesis [4][5][6][7]. Impaired microtubule stability has been consistently observed in many neurodevelopmental disorders such as intellectual disabilities and autism spectrum disorder [8].Stathmin1 is a cytosolic phosphoprotein that functions as a microtubule-destabilizing factor. Stathmin1 destabilizes microtubules by sequestration of α-and β-tubulin heterodimers, inhibiting microtubule polymerization and promoting microtubule catastrophe [9,10]. The microtubule-destabilizing activity of Stathmin1 is sup...
Gene expression profiling in response to nerve injury has been mainly focused on protein functions of coding genes to understand mechanisms of axon regeneration and to identify targets of potential therapeutics for nerve repair. However, the protein functions of several highly injury-induced genes including Gpr151 for regulating the regenerative ability remain unclear. Here we present an alternative approach focused on non-coding functions of the coding genes, which led to the identification of the Gpr151 RNA function as a molecular sponge via its interaction with RNA-binding proteins such as CSDE1. Gpr151 promotes axon regeneration by the function of its 5’- untranslated region (5’UTR) and expression of an engineered form of the 5’UTR improves regenerative capacity in vitro and in vivo in both sciatic nerve and optic nerve injury models. Our data suggest that searching injury-induced coding genes potentially functioning by their non-coding regions is required for the RNA-based gene therapy for improving axon regeneration.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.