Journal article
Knockdown of Fidgetin Improves Regeneration of Injured Axons by a Microtubule-Based Mechanism
The Journal of neuroscience, Vol.39(11), pp.2011-2024
13 Mar 2019
PMCID: PMC6507085
PMID: 30647150
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Fidgetin is a microtubule-severing protein that pares back the labile domains of microtubules in the axon. Experimental depletion of fidgetin results in elongation of the labile domains of microtubules and faster axonal growth. To test whether
knockdown assists axonal regeneration, we plated dissociated adult rat DRGs transduced using AAV5-shRNA-
on a laminin substrate with spots of aggrecan, a growth-inhibitory chondroitin sulfate proteoglycan. This cell culture assay mimics the glial scar formed after CNS injury. Aggrecan is more concentrated at the edge of the spot, such that axons growing from within the spot toward the edge encounter a concentration gradient that causes growth cones to become dystrophic and axons to retract or curve back on themselves.
knockdown resulted in faster-growing axons on both laminin and aggrecan and enhanced crossing of axons from laminin onto aggrecan. Strikingly, axons from within the spot grew more avidly against the inhibitory aggrecan concentration gradient to cross onto laminin, without retracting or curving back. We also tested whether depleting fidgetin improves axonal regeneration
after a dorsal root crush in adult female rats. Whereas control DRG neurons failed to extend axons across the dorsal root entry zone after injury, DRG neurons in which
was knocked down displayed enhanced regeneration of axons across the dorsal root entry zone into the spinal cord. Collectively, these results establish fidgetin as a novel therapeutic target to augment nerve regeneration and provide a workflow template by which microtubule-related targets can be compared in the future.
Here we establish a workflow template from cell culture to animals in which microtubule-based treatments can be tested and compared with one another for their effectiveness in augmenting regeneration of injured axons relevant to spinal cord injury. The present work uses a viral transduction approach to knock down
from rat neurons, which coaxes nerve regeneration by elevating microtubule mass in their axons. Unlike previous strategies using microtubule-stabilizing drugs,
knockdown adds microtubule mass that is labile (rather than stable), thereby better recapitulating the growth status of a developing axon.
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Details
- Title
- Knockdown of Fidgetin Improves Regeneration of Injured Axons by a Microtubule-Based Mechanism
- Creators
- Andrew J Matamoros - Drexel UniversityVeronica J Tom - Drexel UniversityDi Wu - Drexel UniversityYash Rao - Drexel UniversityDavid J Sharp - Albert Einstein College of MedicinePeter W Baas - Drexel University
- Publication Details
- The Journal of neuroscience, Vol.39(11), pp.2011-2024
- Publisher
- Society for Neuroscience
- Grant note
- R01 NS106908 / NINDS NIH HHS R01 NS085426 / NINDS NIH HHS F31 NS103443 / NINDS NIH HHS R01 NS028785 / NINDS NIH HHS R01 GM109909 / NIGMS NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Identifiers
- 991019167811704721
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- Domestic collaboration
- Web of Science research areas
- Neurosciences