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

Yue Qu, Ines Hahn, Meredith Lees, Jill Parkin, André Voelzmann, Karel Dorey, Alex Rathbone, Claire Friel, Viki Allan, Pilar Okenve-Ramos, Natalia Sanchez-Soriano, Andreas Prokop
doi: https://doi.org/10.1101/385658
Yue Qu
1The University of Manchester, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biology, Manchester, UK
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Ines Hahn
1The University of Manchester, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biology, Manchester, UK
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  • For correspondence: Ines.Hahn@manchester.ac.uk
Meredith Lees
1The University of Manchester, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biology, Manchester, UK
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Jill Parkin
1The University of Manchester, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biology, Manchester, UK
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André Voelzmann
1The University of Manchester, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biology, Manchester, UK
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Karel Dorey
1The University of Manchester, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biology, Manchester, UK
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Alex Rathbone
2The University of Nottingham, School of Life Sciences, Faculty of Medicine & Health Sciences, Nottingham, UK
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Claire Friel
2The University of Nottingham, School of Life Sciences, Faculty of Medicine & Health Sciences, Nottingham, UK
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Viki Allan
1The University of Manchester, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biology, Manchester, UK
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Pilar Okenve-Ramos
3Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
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Natalia Sanchez-Soriano
3Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
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Andreas Prokop
1The University of Manchester, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biology, Manchester, UK
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Abstract

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, explorative MTs 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.

Summary statement The cortical collapse factor Efa6 inhibits microtubule polymerising outside axonal bundles. Thereby it limits axon growth and branching, but preserves microtubule bundle organisation crucial for axon maintenance.

Footnotes

  • This version contains important new experiments: (1) New in vitro data show that the MTED binds tubulin and blocks its polymerisation in the absence of other proteins; (2) live imaging and transfected fibroblasts shows that areas enriched with Efa6-FL or Efa6-Nterm::CAAX prevent MTs from elongation; (3) transfection of shot mutant neurons with Efa6-FL rescues their MT disorganisation phenotypes.

  • http://www.prokop.co.uk/Qu+al/RawData.zip

  • http://www.prokop.co.uk/Qu+al/SupplMov.html

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 19, 2019.
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Efa6 protects axons and regulates their growth and branching by inhibiting microtubule polymerisation at the cortex
Yue Qu, Ines Hahn, Meredith Lees, Jill Parkin, André Voelzmann, Karel Dorey, Alex Rathbone, Claire Friel, Viki Allan, Pilar Okenve-Ramos, Natalia Sanchez-Soriano, Andreas Prokop
bioRxiv 385658; doi: https://doi.org/10.1101/385658
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Efa6 protects axons and regulates their growth and branching by inhibiting microtubule polymerisation at the cortex
Yue Qu, Ines Hahn, Meredith Lees, Jill Parkin, André Voelzmann, Karel Dorey, Alex Rathbone, Claire Friel, Viki Allan, Pilar Okenve-Ramos, Natalia Sanchez-Soriano, Andreas Prokop
bioRxiv 385658; doi: https://doi.org/10.1101/385658

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