Cargando…

Efa6 protects axons and regulates their growth and branching by inhibiting microtubule polymerisation at the cortex

Cortical collapse factors affect microtubule (MT) dynamics at the plasma membrane. They play important roles in neurons, as suggested by inhibition of axon growth and regeneration through the ARF activator Efa6 in C. elegans, and by neurodevelopmental disorders linked to the mammalian kinesin Kif21A...

Descripción completa

Detalles Bibliográficos
Autores principales: Qu, Yue, Hahn, Ines, Lees, Meredith, Parkin, Jill, Voelzmann, André, Dorey, Karel, Rathbone, Alex, Friel, Claire T, Allan, Victoria J, Okenve-Ramos, Pilar, Sanchez-Soriano, Natalia, Prokop, Andreas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884004/
https://www.ncbi.nlm.nih.gov/pubmed/31718774
http://dx.doi.org/10.7554/eLife.50319
_version_ 1783474486764371968
author Qu, Yue
Hahn, Ines
Lees, Meredith
Parkin, Jill
Voelzmann, André
Dorey, Karel
Rathbone, Alex
Friel, Claire T
Allan, Victoria J
Okenve-Ramos, Pilar
Sanchez-Soriano, Natalia
Prokop, Andreas
author_facet Qu, Yue
Hahn, Ines
Lees, Meredith
Parkin, Jill
Voelzmann, André
Dorey, Karel
Rathbone, Alex
Friel, Claire T
Allan, Victoria J
Okenve-Ramos, Pilar
Sanchez-Soriano, Natalia
Prokop, Andreas
author_sort Qu, Yue
collection PubMed
description Cortical collapse factors affect microtubule (MT) dynamics at the plasma membrane. They play important roles in neurons, as suggested by inhibition of axon growth and regeneration through the ARF activator Efa6 in C. elegans, and by neurodevelopmental disorders linked to the mammalian kinesin Kif21A. How cortical collapse factors influence axon growth is little understood. Here we studied them, focussing on the function of Drosophila Efa6 in experimentally and genetically amenable fly neurons. First, we show that Drosophila Efa6 can inhibit MTs directly without interacting molecules via an N-terminal 18 amino acid motif (MT elimination domain/MTED) that binds tubulin and inhibits microtubule growth in vitro and cells. If N-terminal MTED-containing fragments are in the cytoplasm they abolish entire microtubule networks of mouse fibroblasts and whole axons of fly neurons. Full-length Efa6 is membrane-attached, hence primarily blocks MTs in the periphery of fibroblasts, and explorative MTs that have left axonal bundles in neurons. Accordingly, loss of Efa6 causes an increase of explorative MTs: in growth cones they enhance axon growth, in axon shafts they cause excessive branching, as well as atrophy through perturbations of MT bundles. Efa6 over-expression causes the opposite phenotypes. Taken together, our work conceptually links molecular and sub-cellular functions of cortical collapse factors to axon growth regulation and reveals new roles in axon branching and in the prevention of axonal atrophy. Furthermore, the MTED delivers a promising tool that can be used to inhibit MTs in a compartmentalised fashion when fusing it to specifically localising protein domains.
format Online
Article
Text
id pubmed-6884004
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher eLife Sciences Publications, Ltd
record_format MEDLINE/PubMed
spelling pubmed-68840042019-12-03 Efa6 protects axons and regulates their growth and branching by inhibiting microtubule polymerisation at the cortex Qu, Yue Hahn, Ines Lees, Meredith Parkin, Jill Voelzmann, André Dorey, Karel Rathbone, Alex Friel, Claire T Allan, Victoria J Okenve-Ramos, Pilar Sanchez-Soriano, Natalia Prokop, Andreas eLife Cell Biology Cortical collapse factors affect microtubule (MT) dynamics at the plasma membrane. They play important roles in neurons, as suggested by inhibition of axon growth and regeneration through the ARF activator Efa6 in C. elegans, and by neurodevelopmental disorders linked to the mammalian kinesin Kif21A. How cortical collapse factors influence axon growth is little understood. Here we studied them, focussing on the function of Drosophila Efa6 in experimentally and genetically amenable fly neurons. First, we show that Drosophila Efa6 can inhibit MTs directly without interacting molecules via an N-terminal 18 amino acid motif (MT elimination domain/MTED) that binds tubulin and inhibits microtubule growth in vitro and cells. If N-terminal MTED-containing fragments are in the cytoplasm they abolish entire microtubule networks of mouse fibroblasts and whole axons of fly neurons. Full-length Efa6 is membrane-attached, hence primarily blocks MTs in the periphery of fibroblasts, and explorative MTs that have left axonal bundles in neurons. Accordingly, loss of Efa6 causes an increase of explorative MTs: in growth cones they enhance axon growth, in axon shafts they cause excessive branching, as well as atrophy through perturbations of MT bundles. Efa6 over-expression causes the opposite phenotypes. Taken together, our work conceptually links molecular and sub-cellular functions of cortical collapse factors to axon growth regulation and reveals new roles in axon branching and in the prevention of axonal atrophy. Furthermore, the MTED delivers a promising tool that can be used to inhibit MTs in a compartmentalised fashion when fusing it to specifically localising protein domains. eLife Sciences Publications, Ltd 2019-11-13 /pmc/articles/PMC6884004/ /pubmed/31718774 http://dx.doi.org/10.7554/eLife.50319 Text en © 2019, Qu et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cell Biology
Qu, Yue
Hahn, Ines
Lees, Meredith
Parkin, Jill
Voelzmann, André
Dorey, Karel
Rathbone, Alex
Friel, Claire T
Allan, Victoria J
Okenve-Ramos, Pilar
Sanchez-Soriano, Natalia
Prokop, Andreas
Efa6 protects axons and regulates their growth and branching by inhibiting microtubule polymerisation at the cortex
title Efa6 protects axons and regulates their growth and branching by inhibiting microtubule polymerisation at the cortex
title_full Efa6 protects axons and regulates their growth and branching by inhibiting microtubule polymerisation at the cortex
title_fullStr Efa6 protects axons and regulates their growth and branching by inhibiting microtubule polymerisation at the cortex
title_full_unstemmed Efa6 protects axons and regulates their growth and branching by inhibiting microtubule polymerisation at the cortex
title_short Efa6 protects axons and regulates their growth and branching by inhibiting microtubule polymerisation at the cortex
title_sort efa6 protects axons and regulates their growth and branching by inhibiting microtubule polymerisation at the cortex
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884004/
https://www.ncbi.nlm.nih.gov/pubmed/31718774
http://dx.doi.org/10.7554/eLife.50319
work_keys_str_mv AT quyue efa6protectsaxonsandregulatestheirgrowthandbranchingbyinhibitingmicrotubulepolymerisationatthecortex
AT hahnines efa6protectsaxonsandregulatestheirgrowthandbranchingbyinhibitingmicrotubulepolymerisationatthecortex
AT leesmeredith efa6protectsaxonsandregulatestheirgrowthandbranchingbyinhibitingmicrotubulepolymerisationatthecortex
AT parkinjill efa6protectsaxonsandregulatestheirgrowthandbranchingbyinhibitingmicrotubulepolymerisationatthecortex
AT voelzmannandre efa6protectsaxonsandregulatestheirgrowthandbranchingbyinhibitingmicrotubulepolymerisationatthecortex
AT doreykarel efa6protectsaxonsandregulatestheirgrowthandbranchingbyinhibitingmicrotubulepolymerisationatthecortex
AT rathbonealex efa6protectsaxonsandregulatestheirgrowthandbranchingbyinhibitingmicrotubulepolymerisationatthecortex
AT frielclairet efa6protectsaxonsandregulatestheirgrowthandbranchingbyinhibitingmicrotubulepolymerisationatthecortex
AT allanvictoriaj efa6protectsaxonsandregulatestheirgrowthandbranchingbyinhibitingmicrotubulepolymerisationatthecortex
AT okenveramospilar efa6protectsaxonsandregulatestheirgrowthandbranchingbyinhibitingmicrotubulepolymerisationatthecortex
AT sanchezsorianonatalia efa6protectsaxonsandregulatestheirgrowthandbranchingbyinhibitingmicrotubulepolymerisationatthecortex
AT prokopandreas efa6protectsaxonsandregulatestheirgrowthandbranchingbyinhibitingmicrotubulepolymerisationatthecortex