Co-targeting myelin inhibitors and CSPGs markedly enhances regeneration of GDNF-stimulated, but not conditioning-lesioned, sensory axons into the spinal cord
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-ass...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/63050 |
| _version_ | 1811180352406814720 |
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| author | Jinbin Zhai Hyukmin Kim Seung Baek Han Meredith Manire Rachel Yoo Shuhuan Pang George M Smith Young-Jin Son |
| author_facet | Jinbin Zhai Hyukmin Kim Seung Baek Han Meredith Manire Rachel Yoo Shuhuan Pang George M Smith Young-Jin Son |
| author_sort | Jinbin Zhai |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T09:01:52Z |
| format | Article |
| id | doaj.art-801649fb2cb447c1b57b2b765a724588 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:01:52Z |
| publishDate | 2021-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-801649fb2cb447c1b57b2b765a7245882022-12-22T04:32:45ZengeLife Sciences Publications LtdeLife2050-084X2021-05-011010.7554/eLife.63050Co-targeting myelin inhibitors and CSPGs markedly enhances regeneration of GDNF-stimulated, but not conditioning-lesioned, sensory axons into the spinal cordJinbin Zhai0Hyukmin Kim1Seung Baek Han2Meredith Manire3Rachel Yoo4Shuhuan Pang5George M Smith6Young-Jin Son7https://orcid.org/0000-0001-5725-9775Shriners Hospitals Pediatric Research Center and Center for Neural Repair and Rehabilitation, Lewis Katz School of Medicine, Temple University, Philadelphia, United States; Center for Neural Repair and Rehabilitation, Lewis Katz School of Medicine, Temple University, Philadelphia, United StatesShriners Hospitals Pediatric Research Center and Center for Neural Repair and Rehabilitation, Lewis Katz School of Medicine, Temple University, Philadelphia, United States; Center for Neural Repair and Rehabilitation, Lewis Katz School of Medicine, Temple University, Philadelphia, United StatesShriners Hospitals Pediatric Research Center and Center for Neural Repair and Rehabilitation, Lewis Katz School of Medicine, Temple University, Philadelphia, United States; Center for Neural Repair and Rehabilitation, Lewis Katz School of Medicine, Temple University, Philadelphia, United StatesShriners Hospitals Pediatric Research Center and Center for Neural Repair and Rehabilitation, Lewis Katz School of Medicine, Temple University, Philadelphia, United States; Center for Neural Repair and Rehabilitation, Lewis Katz School of Medicine, Temple University, Philadelphia, United StatesShriners Hospitals Pediatric Research Center and Center for Neural Repair and Rehabilitation, Lewis Katz School of Medicine, Temple University, Philadelphia, United States; Center for Neural Repair and Rehabilitation, Lewis Katz School of Medicine, Temple University, Philadelphia, United StatesShriners Hospitals Pediatric Research Center and Center for Neural Repair and Rehabilitation, Lewis Katz School of Medicine, Temple University, Philadelphia, United States; Center for Neural Repair and Rehabilitation, Lewis Katz School of Medicine, Temple University, Philadelphia, United StatesShriners Hospitals Pediatric Research Center and Center for Neural Repair and Rehabilitation, Lewis Katz School of Medicine, Temple University, Philadelphia, United States; Center for Neural Repair and Rehabilitation, Lewis Katz School of Medicine, Temple University, Philadelphia, United StatesShriners Hospitals Pediatric Research Center and Center for Neural Repair and Rehabilitation, Lewis Katz School of Medicine, Temple University, Philadelphia, United States; Center for Neural Repair and Rehabilitation, Lewis Katz School of Medicine, Temple University, Philadelphia, United StatesA 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.https://elifesciences.org/articles/63050rhizotomydorsal root injuryDRGNogospinal cord regenerationsensory axon |
| spellingShingle | Jinbin Zhai Hyukmin Kim Seung Baek Han Meredith Manire Rachel Yoo Shuhuan Pang George M Smith Young-Jin Son Co-targeting myelin inhibitors and CSPGs markedly enhances regeneration of GDNF-stimulated, but not conditioning-lesioned, sensory axons into the spinal cord eLife rhizotomy dorsal root injury DRG Nogo spinal cord regeneration sensory axon |
| title | Co-targeting myelin inhibitors and CSPGs markedly enhances regeneration of GDNF-stimulated, but not conditioning-lesioned, sensory axons into the spinal cord |
| title_full | Co-targeting myelin inhibitors and CSPGs markedly enhances regeneration of GDNF-stimulated, but not conditioning-lesioned, sensory axons into the spinal cord |
| title_fullStr | Co-targeting myelin inhibitors and CSPGs markedly enhances regeneration of GDNF-stimulated, but not conditioning-lesioned, sensory axons into the spinal cord |
| title_full_unstemmed | Co-targeting myelin inhibitors and CSPGs markedly enhances regeneration of GDNF-stimulated, but not conditioning-lesioned, sensory axons into the spinal cord |
| title_short | Co-targeting myelin inhibitors and CSPGs markedly enhances regeneration of GDNF-stimulated, but not conditioning-lesioned, sensory axons into the spinal cord |
| title_sort | co targeting myelin inhibitors and cspgs markedly enhances regeneration of gdnf stimulated but not conditioning lesioned sensory axons into the spinal cord |
| topic | rhizotomy dorsal root injury DRG Nogo spinal cord regeneration sensory axon |
| url | https://elifesciences.org/articles/63050 |
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