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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-11-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/50319 |
| _version_ | 1811201379125952512 |
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| author | Yue Qu Ines Hahn Meredith Lees Jill Parkin André Voelzmann Karel Dorey Alex Rathbone Claire T Friel Victoria J Allan Pilar Okenve-Ramos Natalia Sanchez-Soriano Andreas Prokop |
| author_facet | Yue Qu Ines Hahn Meredith Lees Jill Parkin André Voelzmann Karel Dorey Alex Rathbone Claire T Friel Victoria J Allan Pilar Okenve-Ramos Natalia Sanchez-Soriano Andreas Prokop |
| author_sort | Yue Qu |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T02:19:53Z |
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| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:19:53Z |
| publishDate | 2019-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-4f7597d325c748c2846b745dd23b04fa2022-12-22T03:52:08ZengeLife Sciences Publications LtdeLife2050-084X2019-11-01810.7554/eLife.50319Efa6 protects axons and regulates their growth and branching by inhibiting microtubule polymerisation at the cortexYue Qu0Ines Hahn1https://orcid.org/0000-0001-7703-8160Meredith Lees2Jill Parkin3André Voelzmann4https://orcid.org/0000-0002-7682-5637Karel Dorey5https://orcid.org/0000-0003-0846-5286Alex Rathbone6Claire T Friel7https://orcid.org/0000-0001-8395-5301Victoria J Allan8https://orcid.org/0000-0003-4583-0836Pilar Okenve-Ramos9https://orcid.org/0000-0002-7513-6557Natalia Sanchez-Soriano10https://orcid.org/0000-0002-6667-2817Andreas Prokop11https://orcid.org/0000-0001-8482-3298Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, United KingdomManchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, United KingdomManchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, United KingdomManchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, United KingdomManchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, United KingdomFaculty of Biology, Medicine and Health, School of Medical Sciences, The University of Manchester, Manchester, United KingdomSchool of Life Sciences, Faculty of Medicine and Health Sciences, The University of Nottingham, Nottingham, United KingdomSchool of Life Sciences, Faculty of Medicine and Health Sciences, The University of Nottingham, Nottingham, United KingdomManchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, United KingdomDepartment of Cellular and Molecular Physiology,Institute of Translational Medicine, University of Liverpool, Liverpool, United KingdomDepartment of Cellular and Molecular Physiology,Institute of Translational Medicine, University of Liverpool, Liverpool, United KingdomManchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, United KingdomCortical 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.https://elifesciences.org/articles/50319Drosophilaneurodegenerationaxonscytoskeletonmicrotubules |
| spellingShingle | Yue Qu Ines Hahn Meredith Lees Jill Parkin André Voelzmann Karel Dorey Alex Rathbone Claire T Friel Victoria J Allan Pilar Okenve-Ramos Natalia Sanchez-Soriano Andreas Prokop Efa6 protects axons and regulates their growth and branching by inhibiting microtubule polymerisation at the cortex eLife Drosophila neurodegeneration axons cytoskeleton microtubules |
| 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 | Drosophila neurodegeneration axons cytoskeleton microtubules |
| url | https://elifesciences.org/articles/50319 |
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