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

Author:

Zhai Jinbin12,Kim Hyukmin12,Han Seung Baek12,Manire Meredith12,Yoo Rachel12,Pang Shuhuan12,Smith George M12,Son Young-Jin12ORCID

Affiliation:

1. Shriners Hospitals Pediatric Research Center and Center for Neural Repair and Rehabilitation, Lewis Katz School of Medicine, Temple University, Philadelphia, United States

2. Center for Neural Repair and Rehabilitation, Lewis Katz School of Medicine, Temple University, Philadelphia, 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.

Funder

National Institute of Neurological Disorders and Stroke

Shriners Hospitals for Children

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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