Co-targeting myelin inhibitors and CSPGs markedly enhances regeneration of GDNF-stimulated, but not conditioning-lesioned, sensory axons into the spinal cord
- Temple University, United States
Abstract
A major barrier to intraspinal regeneration after dorsal root (DR) injury is the DR entry zone (DREZ), the CNS/PNS interface. DR axons stop regenerating at the DREZ, even if regenerative capacity is increased by a nerve conditioning lesion. This potent blockade has long been attributed to myelin-associated inhibitors and CSPGs, but incomplete lesions and conflicting reports have prevented conclusive agreement. Here we evaluated DR regeneration in mice, using novel strategies to facilitate complete lesions and analyses, selective tracing of proprioceptive and mechanoreceptive axons, and the first simultaneous targeting of Nogo/Reticulon-4, MAG, OMgp, CSPGs and GDNF. Co-eliminating myelin inhibitors and CSPGs elicited regeneration of only a few conditioning-lesioned DR axons across the DREZ. Their absence, however, markedly and synergistically enhanced regeneration of GDNF-stimulated axons, highlighting the importance of sufficiently elevating intrinsic growth capacity. We also conclude that myelin inhibitors and CSPGs are not the primary mechanism stopping axons at the DREZ.
Data availability
Numerical data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been submitted for Figures 3, 4, 5,6, 6-S1, 7, 8, 9.
Article and author information
Author details
Funding
National Institute of Neurological Disorders and Stroke (NS079631)
- Young-Jin Son
Shriners Hospitals for Children (86600,84050)
- Young-Jin Son
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Lilianna Solnica-Krezel, Washington University School of Medicine, United States
Ethics
Animal experimentation: All animal care and procedures were conducted in accordance with the National Research Council's Guide for the Care and Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committee at Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA. (animal protocol #4919),
Version history
- Received: September 11, 2020
- Accepted: May 3, 2021
- Accepted Manuscript published: May 4, 2021 (version 1)
- Version of Record published: May 21, 2021 (version 2)
Copyright
© 2021, Zhai et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Co-targeting myelin inhibitors and CSPGs markedly enhances regeneration of GDNF-stimulated, but not conditioning-lesioned, sensory axons into the spinal cord
eLife 10:e63050.
https://doi.org/10.7554/eLife.63050
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