Engineering neuronal growth cones to promote axon regeneration over inhibitory molecules

Eun Mi Hur, In Hong Yang, Deok Ho Kim, Justin Byun, Saijilafu, Wen Lin Xu, Philip R. Nicovich, Raymond Cheong, Andre Levchenko, Nitish Thakor, Feng Quan Zhoua

Research output: Contribution to journalArticle

Abstract

Neurons in the central nervous system (CNS) fail to regenerate axons after injuries due to the diminished intrinsic axon growth capacity of mature neurons and the hostile extrinsic environment composed of a milieu of inhibitory factors. Recent studies revealed that targeting a particular group of extracellular inhibitory factors is insufficient to trigger long-distance axon regeneration. Instead of antagonizing the growing list of impediments, tackling a common target that mediates axon growth inhibition offers an alternative strategy to promote axon regeneration. Neuronal growth cone, the machinery that derives axon extension, is the final converging target of most, if not all, growth impediments in the CNS. In this study, we aim to promote axon growth by directly targeting the growth cone. Here we report that pharmacological inhibition or genetic silencing of nonmuscle myosin II (NMII) markedly accelerates axon growth over permissive and non-permissive substrates, including major CNS inhibitors such as chondroitin sulfate proteoglycans and myelin-associated inhibitors. We find that NMII inhibition leads to the reorganization of both actin and microtubules (MTs) in the growth cone, resulting in MT reorganization that allows rapid axon extension over inhibitory substrates. In addition to enhancing axon extension, we show that local blockade of NMII activity in axons is sufficient to trigger axons to grow across the permissive-inhibitory border. Together, our study proposes NMII and growth cone cytoskeletal components as effective targets for promoting axon regeneration.

Original languageEnglish (US)
Pages (from-to)5057-5062
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number12
DOIs
StatePublished - Mar 22 2011

Keywords

  • Glial scar
  • Multi-compartment neuronal culture chamber
  • Myelin

ASJC Scopus subject areas

  • General

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