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.

Metrics

  • 798
    Page views
  • 121
    Downloads
  • 4
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Neuroscience
    Kevin Vinberg, Jörgen Rosén ... Fredrik Ahs
    Research Article Updated

    Understanding the neural basis for individual differences in the skin conductance response (SCR) during discriminative fear conditioning may inform on our understanding of autonomic regulation in fear-related psychopathology. Previous region-of-interest (ROI) analyses have implicated the amygdala in regulating conditioned SCR, but whole brain analyses are lacking. This study examined correlations between individual differences in SCR during discriminative fear conditioning to social stimuli and neural activity throughout the brain, by using data from a large functional magnetic resonance imaging study of twins (N = 285 individuals). Results show that conditioned SCR correlates with activity in the dorsal anterior cingulate cortex/anterior midcingulate cortex, anterior insula, bilateral temporoparietal junction, right frontal operculum, bilateral dorsal premotor cortex, right superior parietal lobe, and midbrain. A ROI analysis additionally showed a positive correlation between amygdala activity and conditioned SCR in line with previous reports. We suggest that the observed whole brain correlates of SCR belong to a large-scale midcingulo-insular network related to salience detection and autonomic-interoceptive processing. Altered activity within this network may underlie individual differences in conditioned SCR and autonomic aspects of psychopathology.

    1. Neuroscience
    Rong Zhao, Stacy D Grunke ... Joanna L Jankowsky
    Research Article

    Neurodegenerative diseases are characterized by selective vulnerability of distinct cell populations; however, the cause for this specificity remains elusive. Here we show that entorhinal cortex layer 2 (EC2) neurons are unusually vulnerable to prolonged neuronal inactivity compared with neighboring regions of the temporal lobe, and that reelin+ stellate cells connecting EC with the hippocampus are preferentially susceptible within the EC2 population. We demonstrate that neuronal death after silencing can be elicited through multiple independent means of activity inhibition, and that preventing synaptic release, either alone or in combination with electrical shunting, is sufficient to elicit silencing-induced degeneration. Finally, we discovered that degeneration following synaptic silencing is governed by competition between active and inactive cells, which is a circuit refinement process traditionally thought to end early in postnatal life. Our data suggests that the developmental window for wholesale circuit plasticity may extend into adulthood for specific brain regions. We speculate that this sustained potential for remodeling by entorhinal neurons may support lifelong memory but renders them vulnerable to prolonged activity changes in disease.