Affordable Access

deepdyve-link
Publisher Website

The role of RhoA in retrograde neuronal death and axon regeneration after spinal cord injury.

Authors
  • Hu, Jianli1
  • Zhang, Guixin1
  • Rodemer, William1
  • Jin, Li-Qing1
  • Shifman, Michael1
  • Selzer, Michael E2
  • 1 Shriners Hospitals Pediatric Research Center (Center for Neural Repair and Rehabilitation), Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, Philadelphia, PA 19140, USA.
  • 2 Shriners Hospitals Pediatric Research Center (Center for Neural Repair and Rehabilitation), Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, Philadelphia, PA 19140, USA; Dept. of Neurology, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, Philadelphia, PA 19140, USA. Electronic address: [email protected]
Type
Published Article
Journal
Neurobiology of Disease
Publisher
Elsevier
Publication Date
Feb 01, 2017
Volume
98
Pages
25–35
Identifiers
DOI: 10.1016/j.nbd.2016.11.006
PMID: 27888137
Source
Medline
Keywords
License
Unknown

Abstract

Paralysis following spinal cord injury (SCI) is due to interruption of axons and their failure to regenerate. It has been suggested that the small GTPase RhoA may be an intracellular signaling convergence point for several types of growth-inhibiting extracellular molecules. Even if this is true in vitro, it is not clear from studies in mammalian SCI, whether the effects of RhoA manipulations on axon growth in vivo are due to a RhoA-mediated inhibition of true regeneration or only of collateral sprouting from spared axons, since work on SCI generally is performed with partial injury models. RhoA also has been implicated in local neuronal apoptosis after SCI, but whether this reflects an effect on axotomy-induced cell death or an effect on other pathological mechanisms is not known. In order to resolve these ambiguities, we studied the effects of RhoA knockdown in the sea lamprey central nervous system (CNS), where after complete spinal cord transection (TX), robust but incomplete regeneration of large axons belonging to individually identified reticulospinal (RS) neurons occurs, and where some RS neurons show unambiguous delayed retrograde apoptosis after axotomy. RhoA protein was detected in neurons and axons of the lamprey brain and spinal cord, and its expression was increased post-TX. Knockdown of RhoA in vivo by retrogradely-delivered morpholino antisense oligonucleotides (MOs) to the RS neurons significantly reduced retrograde apoptosis signaling in identified RS neurons post-SCI, as indicated by Fluorochrome Labeled Inhibitor of Caspases (FLICA) in brain wholemounts. In individual RS neurons, the reduction of caspase activation by RhoA knockdown began at 2weeks post-TX and was still seen at 8weeks. RhoA knockdown slowed axon retraction and possibly increased early axon regeneration in the proximal stump. The number of axons regenerating beyond the lesion more than 5mm at 10weeks post-TX also was increased. Thus RhoA knockdown both enhanced true axon regeneration and inhibited retrograde apoptosis signaling after SCI.

Report this publication

Statistics

Seen <100 times