Branch-Specific Microtubule Destabilization Mediates Axon Branch Loss During Neuromuscular Synapse Elimination

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2016 Oct 25

PMID 27773584

Citations 53

Authors

Monika S Brill

Tatjana Kleele

Laura Ruschkies

Mengzhe Wang

Natalia A Marahori

Miriam S Reuter

Torben J Hausrat

Emily Weigand

Matthew Fisher

Andrea Ahles

Stefan Engelhardt

Derron L Bishop

Matthias Kneussel

Thomas Misgeld

Affiliations

Soon will be listed here.

Abstract

Developmental axon remodeling is characterized by the selective removal of branches from axon arbors. The mechanisms that underlie such branch loss are largely unknown. Additionally, how neuronal resources are specifically assigned to the branches of remodeling arbors is not understood. Here we show that axon branch loss at the developing mouse neuromuscular junction is mediated by branch-specific microtubule severing, which results in local disassembly of the microtubule cytoskeleton and loss of axonal transport in branches that will subsequently dismantle. Accordingly, pharmacological microtubule stabilization delays neuromuscular synapse elimination. This branch-specific disassembly of the cytoskeleton appears to be mediated by the microtubule-severing enzyme spastin, which is dysfunctional in some forms of upper motor neuron disease. Our results demonstrate a physiological role for a neurodegeneration-associated modulator of the cytoskeleton, reveal unexpected cell biology of branch-specific axon plasticity and underscore the mechanistic similarities of axon loss in development and disease.

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References

Yu W, Qiang L, Solowska J, Karabay A, Korulu S, Baas P . The microtubule-severing proteins spastin and katanin participate differently in the formation of axonal branches. Mol Biol Cell. 2008; 19(4):1485-98. PMC: 2291400. DOI: 10.1091/mbc.e07-09-0878. View

Riley D . Ultrastructural evidence for axon retraction during the spontaneous elimination of polyneuronal innervation of the rat soleus muscle. J Neurocytol. 1981; 10(3):425-40. DOI: 10.1007/BF01262414. View

Zempel H, Luedtke J, Kumar Y, Biernat J, Dawson H, Mandelkow E . Amyloid-β oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin. EMBO J. 2013; 32(22):2920-37. PMC: 3831312. DOI: 10.1038/emboj.2013.207. View

Fletcher D, Mullins R . Cell mechanics and the cytoskeleton. Nature. 2010; 463(7280):485-92. PMC: 2851742. DOI: 10.1038/nature08908. View

Williams D, Truman J . Cellular mechanisms of dendrite pruning in Drosophila: insights from in vivo time-lapse of remodeling dendritic arborizing sensory neurons. Development. 2005; 132(16):3631-42. DOI: 10.1242/dev.01928. View

Hellal F, Hurtado A, Ruschel J, Flynn K, Laskowski C, Umlauf M . Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury. Science. 2011; 331(6019):928-31. PMC: 3330754. DOI: 10.1126/science.1201148. View

Kanamori T, Kanai M, Dairyo Y, Yasunaga K, Morikawa R, Emoto K . Compartmentalized calcium transients trigger dendrite pruning in Drosophila sensory neurons. Science. 2013; 340(6139):1475-8. DOI: 10.1126/science.1234879. View

Stepanova T, Slemmer J, Hoogenraad C, Lansbergen G, Dortland B, De Zeeuw C . Visualization of microtubule growth in cultured neurons via the use of EB3-GFP (end-binding protein 3-green fluorescent protein). J Neurosci. 2003; 23(7):2655-64. PMC: 6742099. View

Janke C, Bulinski J . Post-translational regulation of the microtubule cytoskeleton: mechanisms and functions. Nat Rev Mol Cell Biol. 2011; 12(12):773-86. DOI: 10.1038/nrm3227. View

10.

Fanara P, Banerjee J, Hueck R, Harper M, Awada M, Turner H . Stabilization of hyperdynamic microtubules is neuroprotective in amyotrophic lateral sclerosis. J Biol Chem. 2007; 282(32):23465-72. DOI: 10.1074/jbc.M703434200. View

11.

Cichon J, Gan W . Branch-specific dendritic Ca(2+) spikes cause persistent synaptic plasticity. Nature. 2015; 520(7546):180-5. PMC: 4476301. DOI: 10.1038/nature14251. View

12.

Havlicek S, Kohl Z, Mishra H, Prots I, Eberhardt E, Denguir N . Gene dosage-dependent rescue of HSP neurite defects in SPG4 patients' neurons. Hum Mol Genet. 2014; 23(10):2527-41. PMC: 3990156. DOI: 10.1093/hmg/ddt644. View

13.

Riccomagno M, Kolodkin A . Sculpting neural circuits by axon and dendrite pruning. Annu Rev Cell Dev Biol. 2015; 31:779-805. PMC: 4668927. DOI: 10.1146/annurev-cellbio-100913-013038. View

14.

Walsh M, Gan W, Feng G, Sanes J, Lichtman J . Asynchronous synapse elimination in neonatal motor units: studies using GFP transgenic mice. Neuron. 2001; 31(3):381-94. DOI: 10.1016/s0896-6273(01)00383-x. View

15.

Luo L, OLeary D . Axon retraction and degeneration in development and disease. Annu Rev Neurosci. 2005; 28:127-56. DOI: 10.1146/annurev.neuro.28.061604.135632. View

16.

Baas P, Rao A, Matamoros A, Leo L . Stability properties of neuronal microtubules. Cytoskeleton (Hoboken). 2016; 73(9):442-60. PMC: 5541393. DOI: 10.1002/cm.21286. View

17.

Das V, Miller J . Microtubule stabilization by peloruside A and paclitaxel rescues degenerating neurons from okadaic acid-induced tau phosphorylation. Eur J Neurosci. 2012; 35(11):1705-17. DOI: 10.1111/j.1460-9568.2012.08084.x. View

18.

Wood J, Landers J, Bingley M, McDermott C, Thomas-McArthur V, Gleadall L . The microtubule-severing protein Spastin is essential for axon outgrowth in the zebrafish embryo. Hum Mol Genet. 2006; 15(18):2763-71. DOI: 10.1093/hmg/ddl212. View

19.

Yaron A, Schuldiner O . Common and Divergent Mechanisms in Developmental Neuronal Remodeling and Dying Back Neurodegeneration. Curr Biol. 2016; 26(13):R628-R639. PMC: 5086086. DOI: 10.1016/j.cub.2016.05.025. View

20.

dYdewalle C, Krishnan J, Chiheb D, Van Damme P, Irobi J, Kozikowski A . HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease. Nat Med. 2011; 17(8):968-74. DOI: 10.1038/nm.2396. View