Ndel1 Promotes Axon Regeneration via Intermediate Filaments

Cory Toth,Wei-Qiao Liu,Jose Martinez,Su Yeon Shim,Yulan Jiang,Minh Dang Nguyen,Douglas Zochodne,Camille Belzil,Jian Wang,Gernot Neumayer

doi:10.1371/journal.pone.0002014

Abstract

Failure of axons to regenerate following acute or chronic neuronal injury is attributed to both the inhibitory glial environment and deficient intrinsic ability to re-grow. However, the underlying mechanisms of the latter remain unclear. In this study, we have investigated the role of the mammalian homologue of aspergillus nidulans NudE, Ndel1, emergently viewed as an integrator of the cytoskeleton, in axon regeneration. Ndel1 was synthesized de novo and upregulated in crushed and transected sciatic nerve axons, and, upon injury, was strongly associated with neuronal form of the intermediate filament (IF) Vimentin while dissociating from the mature neuronal IF (Neurofilament) light chain NF-L. Consistent with a role for Ndel1 in the conditioning lesion-induced neurite outgrowth of Dorsal Root Ganglion (DRG) neurons, the long lasting in vivo formation of the neuronal Ndel1/Vimentin complex was associated with robust axon regeneration. Furthermore, local silencing of Ndel1 in transected axons by siRNA severely reduced the extent of regeneration in vivo. Thus, Ndel1 promotes axonal regeneration; activating this endogenous repair mechanism may enhance neuroregeneration during acute and chronic axonal degeneration.

Highlights

Axonal injury, the underlying cause of spinal cord disability, neuropathies and neurodegenerative disorders, triggers changes in gene expression and protein complexes within neurons and glia
Axonal localization of the Ndel1/Vimentin complex Ndel1 and Vimentin contribute to neurite outgrowth, a readout for axonal regeneration [20,21,22,24,25,26]
Vimentin is expressed in both glia and neurons and the intermediate filament (IF) exhibits both pro- and anti-regenerative properties

Summary

Introduction

The underlying cause of spinal cord disability, neuropathies and neurodegenerative disorders, triggers changes in gene expression and protein complexes within neurons and glia. While some of these changes favor axonal regeneration, other signals drastically dampen the protective response, resulting in either failed or incomplete functional recovery. The developmental pattern of IFs resumes: IF proteins that decline during development are reexpressed [11,12,13,14,15,16,17] This change in gene expression is thought to contribute to neuronal plasticity during regeneration. The mechanisms of cytoskeletal remodeling within injured axons remain poorly defined

Methods

Results

Discussion

Conclusion