Dataset Information

?Pix-d promotes tubulin acetylation and neurite outgrowth through a PAK/Stathmin1 signaling pathway.

ABSTRACT: Microtubules are a major cytoskeletal component of neurites, and the regulation of microtubule stability is essential for neurite morphogenesis. ?Pix (ARHGEF7) is a guanine nucleotide exchange factor for the small GTPases Rac1 and Cdc42, which modulate the organization of actin filaments and microtubules. ?Pix is expressed as alternatively spliced variants, including the ubiquitous isoform ?Pix-a and the neuronal isoforms ?Pix-b and ?Pix-d, but the function of the neuronal isoforms remains unclear. Here, we reveal the novel role of ?Pix neuronal isoforms in regulating tubulin acetylation and neurite outgrowth. At DIV4, hippocampal neurons cultured from ?Pix neuronal isoform knockout (?Pix-NIKO) mice exhibit defects in neurite morphology and tubulin acetylation, a type of tubulin modification which often labels stable microtubules. Treating ?Pix-NIKO neurons with paclitaxel, which stabilizes the microtubules, or reintroducing either neuronal ?Pix isoform to the KO neurons overcomes the impairment in neurite morphology and tubulin acetylation, suggesting that neuronal ?Pix isoforms may promote microtubule stabilization during neurite development. ?Pix-NIKO neurons also exhibit lower phosphorylation levels for Stathmin1, a microtubule-destabilizing protein, at Ser16. Expressing either ?Pix neuronal isoform in the ?Pix-NIKO neurons restores Stathmin1 phosphorylation levels, with ?Pix-d having a greater effect than ?Pix-b. Furthermore, we find that the recovery of neurite length and Stathmin1 phosphorylation via ?Pix-d expression requires PAK kinase activity. Taken together, our study demonstrates that ?Pix-d regulates the phosphorylation of Stathmin1 in a PAK-dependent manner and that neuronal ?Pix isoforms promote tubulin acetylation and neurite morphogenesis during neuronal development.

SUBMITTER: Kwon Y

PROVIDER: S-EPMC7135283 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Kwon Younghee Y Jeon Ye Won YW Kwon Minjae M Cho Yongcheol Y Park Dongeun D Shin Jung Eun JE

PloS one 20200406 4

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 uncle ...[more]

PMID: 32251425

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Project description:BACKGROUND: In early vertebrate development, embryonic tissues modulate cell adhesiveness and acto-myosin contractility to correctly orchestrate the complex processes of gastrulation. E-cadherin (E-cadh) is the earliest expressed cadherin and is needed in the mesendodermal progenitors for efficient migration. Regulatory mechanisms involving directed E-cadh trafficking have been invoked downstream of Wnt11/5 signaling. This non-canonical Wnt pathway regulates RhoA-ROK/DAAM1 to control the acto-myosin network. However, in this context nothing is known of the intracellular signals that participate in the correct localization of E-cadh, other than a need for Rab5c signaling. METHODOLOGY/PRINCIPAL FINDINGS: By studying loss of Chp induced by morpholino-oligonucleotide injection in zebrafish, we find that the vertebrate atypical Rho-GTPase Chp is essential for the proper disposition of cells in the early embryo. The underlying defect is not leading edge F-actin assembly (prominent in the cells of the envelope layer), but rather the failure to localize E-cadh and beta-catenin at the adherens junctions. Loss of Chp results in delayed epiboly that can be rescued by mRNA co-injection, and phenocopies zebrafish E-cadh mutants. This new signaling pathway involves activation of an effector kinase PAK, and involvement of the adaptor PAK-interacting exchange factor PIX. Loss of signaling by any of the three components results in similar underlying defects, which is most prominent in the epithelial-like envelope layer. CONCLUSIONS/SIGNIFICANCE: Our current study uncovers a developmental pathway involving Chp/PAK/PIX signaling, which helps co-ordinate E-cadh disposition to promote proper cell adhesiveness, and coordinate movements of the three major cell layers in epiboly. Our data shows that without Chp signaling, E-cadh shifts to intracellular vesicles rather than the adhesive contacts needed for directed cell movement. These events may mirror the requirement for PAK2 signaling essential for the proper formation of the blood-brain barrier.

Dataset Information

?Pix-d promotes tubulin acetylation and neurite outgrowth through a PAK/Stathmin1 signaling pathway.

Publications

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

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