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Periodic actin structures in neuronal axons are required to maintain microtubules

Yue Qu, Ines Hahn, Stephen Webb, Simon P. Pearce, View ORCID ProfileAndreas Prokop
doi: https://doi.org/10.1101/049379
Yue Qu
1The University of Manchester, Faculty of Biology, Medicine and Health, Michael Smith Building, Oxford 5 Road, Manchester M13 9PT, United Kingdom
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Ines Hahn
1The University of Manchester, Faculty of Biology, Medicine and Health, Michael Smith Building, Oxford 5 Road, Manchester M13 9PT, United Kingdom
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Stephen Webb
2Science and Technology Facilities Council, Research Complex at Harwell, Rutherford Appleton 7 Laboratory, Harwell Campus Didcot, OX11 0QX, UK
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Simon P. Pearce
1The University of Manchester, Faculty of Biology, Medicine and Health, Michael Smith Building, Oxford 5 Road, Manchester M13 9PT, United Kingdom
3The University of Manchester, School of Mathematics, Alan Turing Building, Oxford Road, Manchester 9 M13 9PL, UK
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Andreas Prokop
1The University of Manchester, Faculty of Biology, Medicine and Health, Michael Smith Building, Oxford 5 Road, Manchester M13 9PT, United Kingdom
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  • ORCID record for Andreas Prokop
  • For correspondence: Andreas.Prokop@manchester.ac.uk
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Summary

Axons are the cable-like neuronal processes wiring the nervous system. They contain parallel bundles of microtubules as structural backbones, surrounded by regularly-spaced actin rings termed the periodic membrane skeleton (PMS). Despite being an evolutionarily-conserved, ubiquitous, highly-ordered feature of axons, the function of PMS is unknown. Here we studied PMS abundance, organisation and function, combining versatile Drosophila genetics with super-resolution microscopy and various functional readouts. Analyses with 11 different actin regulators and 3 actin-targeting drugs suggest PMS to contain short actin filaments which are depolymerisation resistant and sensitive to spectrin, adducin and nucleator deficiency - consistent with microscopy-derived models proposing PMS as specialised cortical actin. Upon actin removal we observed gaps in microtubule bundles, reduced microtubule polymerisation and reduced axon numbers suggesting a role of PMS in microtubule organisation. These effects become strongly enhanced when carried out in neurons lacking the microtubule-stabilising protein Short stop (Shot). Combining the aforementioned actin manipulations with Shot deficiency revealed a close correlation between PMS abundance and microtubule regulation, consistent with a model in which PMS-dependent microtubule polymerisation contributes to their maintenance in axons. We discuss potential implications of this novel PMS function along axon shafts for axon maintenance and regeneration.

Significance statement Axons are cable-like neuronal processes that are up to a meter long in humans. These delicate structures often need to be maintained for an organism’s lifetime, i.e. up to a century in humans. Unsurprisingly, we gradually lose about 50% of axons as we age. Bundles of microtubules form the structural backbones and highways for life-sustaining transport within axons, and maintenance of these bundles is essential for axonal longevity. However, the mechanisms which actively maintain axonal microtubules are poorly understood. Here we identify cortical actin as an important factor maintaining microtubule polymerisation in axons. This finding provides potential explanations for the previously identified, but unexplained, links between mutations in genes encoding cortical actin regulators and neurodegeneration.

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Posted October 18, 2016.
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Periodic actin structures in neuronal axons are required to maintain microtubules
Yue Qu, Ines Hahn, Stephen Webb, Simon P. Pearce, Andreas Prokop
bioRxiv 049379; doi: https://doi.org/10.1101/049379
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Periodic actin structures in neuronal axons are required to maintain microtubules
Yue Qu, Ines Hahn, Stephen Webb, Simon P. Pearce, Andreas Prokop
bioRxiv 049379; doi: https://doi.org/10.1101/049379

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