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Integrin-Driven Axon Regeneration in the Spinal Cord Activates a Distinctive CNS Regeneration Program.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Cheah, Menghon 
Cheng, Yuyan 
Petrova, Veselina 
Cimpean, Anda 
Jendelova, Pavla 

Abstract

The peripheral branch of sensory dorsal root ganglion (DRG) neurons regenerates readily after injury unlike their central branch in the spinal cord. However, extensive regeneration and reconnection of sensory axons in the spinal cord can be driven by the expression of α9 integrin and its activator kindlin-1 (α9k1), which enable axons to interact with tenascin-C. To elucidate the mechanisms and downstream pathways affected by activated integrin expression and central regeneration, we conducted transcriptomic analyses of adult male rat DRG sensory neurons transduced with α9k1, and controls, with and without axotomy of the central branch. Expression of α9k1 without the central axotomy led to upregulation of a known PNS regeneration program, including many genes associated with peripheral nerve regeneration. Coupling α9k1 treatment with dorsal root axotomy led to extensive central axonal regeneration. In addition to the program upregulated by α9k1 expression, regeneration in the spinal cord led to expression of a distinctive CNS regeneration program, including genes associated with ubiquitination, autophagy, endoplasmic reticulum (ER), trafficking, and signaling. Pharmacological inhibition of these processes blocked the regeneration of axons from DRGs and human iPSC-derived sensory neurons, validating their causal contributions to sensory regeneration. This CNS regeneration-associated program showed little correlation with either embryonic development or PNS regeneration programs. Potential transcriptional drivers of this CNS program coupled to regeneration include Mef2a, Runx3, E2f4, and Yy1. Signaling from integrins primes sensory neurons for regeneration, but their axon growth in the CNS is associated with an additional distinctive program that differs from that involved in PNS regeneration.SIGNIFICANCE STATEMENT Restoration of neurologic function after spinal cord injury has yet to be achieved in human patients. To accomplish this, severed nerve fibers must be made to regenerate. Reconstruction of nerve pathways has not been possible, but recently, a method for stimulating long-distance axon regeneration of sensory fibers in rodents has been developed. This research uses profiling of messenger RNAs in the regenerating sensory neurons to discover which mechanisms are activated. This study shows that the regenerating neurons initiate a novel CNS regeneration program which includes molecular transport, autophagy, ubiquitination, and modulation of the endoplasmic reticulum (ER). The study identifies mechanisms that neurons need to activate to regenerate their nerve fibers.

Description

Keywords

autophagy, axon regeneration, integrin, sensory, signaling, spinal cord, Rats, Humans, Male, Animals, Axons, Integrins, Nerve Regeneration, Rats, Sprague-Dawley, Spinal Cord, Spinal Cord Injuries, Ganglia, Spinal, Sensory Receptor Cells

Journal Title

J Neurosci

Conference Name

Journal ISSN

0270-6474
1529-2401

Volume Title

Publisher

Society for Neuroscience
Sponsorship
International Foundation for Research in Paraplegia (IRP) (P172)
Medical Research Council (MR/R004463/1)
Medical Research Council (MR/R004544/1)
Fight for Sight (5123 / 5124)
MRC (MR/V002694/1)
Fight for Sight (5119 / 5120)
Medical Research Council (MR/R004544/1 and MR/R004463/1), NWO (013-16-002), Fight for Sight (5065/5066, 5119/5120 and 5123/5124), Wings for Life (WFL GB-04/19), Czech Ministry of Education (CZ.02.1.01/0.0./0.0/15_003/0000419), ERA-NET NEURON AxonRepair, International Foundation for Research in Paraplegia P172, National Institutes of Health R35NS105076, and Dr Miriam and Sheldon G Adelson Medical Research Foundation