Co-targeting myelin inhibitors and CSPGs markedly enhances regeneration of GDNF-stimulated, but not conditioning-lesioned, sensory axons into the spinal cord

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

  1. Jinbin Zhai

    Shriners Hospitals Pediatric Research Center, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Hyukmin Kim

    Shriners Hospitals Pediatric Research Center, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Seung Baek Han

    Shriners Hospitals Pediatric Research Center, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Meredith Manire

    Shriners Hospitals Pediatric Research Center, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Rachel Yoo

    Shriners Hospitals Pediatric Research Center, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Shuhuan Pang

    Shriners Hospitals Pediatric Research Center, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. George M Smith

    Shriners Hospitals Pediatric Research Center, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Young-Jin Son

    Shriners Hospitals Pediatric Research Center, Temple University, Philadelphia, United States
    For correspondence
    yson@temple.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5725-9775

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.

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),

Reviewing Editor

  1. Lilianna Solnica-Krezel, Washington University School of Medicine, United States

Publication history

  1. Received: September 11, 2020
  2. Accepted: May 3, 2021
  3. Accepted Manuscript published: May 4, 2021 (version 1)
  4. 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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  1. Jinbin Zhai
  2. Hyukmin Kim
  3. Seung Baek Han
  4. Meredith Manire
  5. Rachel Yoo
  6. Shuhuan Pang
  7. George M Smith
  8. Young-Jin Son
(2021)
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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