βPix-d promotes tubulin acetylation and neurite outgrowth through a PAK/Stathmin1 signaling pathway

PLoS One. 2020 Apr 6;15(4):e0230814. doi: 10.1371/journal.pone.0230814. eCollection 2020.

Abstract

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 βPix-d, 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 microtubule-destabilizing 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Actin Cytoskeleton / metabolism
  • Animals
  • Cell Cycle Proteins / metabolism
  • Cells, Cultured
  • Female
  • Hippocampus / metabolism
  • Hippocampus / physiology
  • Male
  • Mice
  • Mice, Knockout
  • Microtubules / metabolism
  • Neurites / metabolism
  • Neurites / physiology
  • Neuronal Outgrowth / physiology*
  • Neurons / metabolism
  • Neurons / physiology
  • Phosphorylation / physiology
  • Protein Isoforms / metabolism
  • Protein Isoforms / physiology
  • Rho Guanine Nucleotide Exchange Factors / metabolism*
  • Signal Transduction / physiology*
  • Stathmin / metabolism*
  • Tubulin / metabolism*
  • p21-Activated Kinases / metabolism*
  • rac1 GTP-Binding Protein / metabolism*

Substances

  • Cell Cycle Proteins
  • Protein Isoforms
  • Rho Guanine Nucleotide Exchange Factors
  • Stathmin
  • Stmn1 protein, mouse
  • Tubulin
  • p21-Activated Kinases
  • rac1 GTP-Binding Protein

Grants and funding

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF-2016R1D1A1B03934362 and NRF-2017R1A2B4006259) to D.P. and the Korea Research Fellowship (NRF-2015H1D3A1066313) and a National Research Foundation of Korea grant (NRF-2017R1C1B2008356) to J.E.S. National Research Foundation of Korea website: www.nrf.re.kr The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.