Accelerating axonal growth promotes motor recovery after peripheral nerve injury in mice
Chi Him Eddie Ma, … , Dan Geschwind, Clifford J. Woolf
Chi Him Eddie Ma, … , Dan Geschwind, Clifford J. Woolf
Published October 3, 2011
Citation Information: J Clin Invest. 2011;121(11):4332-4347. https://doi.org/10.1172/JCI58675.
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Research Article

Accelerating axonal growth promotes motor recovery after peripheral nerve injury in mice

Abstract

Although peripheral nerves can regenerate after injury, proximal nerve injury in humans results in minimal restoration of motor function. One possible explanation for this is that injury-induced axonal growth is too slow. Heat shock protein 27 (Hsp27) is a regeneration-associated protein that accelerates axonal growth in vitro. Here, we have shown that it can also do this in mice after peripheral nerve injury. While rapid motor and sensory recovery occurred in mice after a sciatic nerve crush injury, there was little return of motor function after sciatic nerve transection, because of the delay in motor axons reaching their target. This was not due to a failure of axonal growth, because injured motor axons eventually fully re-extended into muscles and sensory function returned; rather, it resulted from a lack of motor end plate reinnervation. Tg mice expressing high levels of Hsp27 demonstrated enhanced restoration of motor function after nerve transection/resuture by enabling motor synapse reinnervation, but only within 5 weeks of injury. In humans with peripheral nerve injuries, shorter wait times to decompression surgery led to improved functional recovery, and, while a return of sensation occurred in all patients, motor recovery was limited. Thus, absence of motor recovery after nerve damage may result from a failure of synapse reformation after prolonged denervation rather than a failure of axonal growth.

Authors

Chi Him Eddie Ma, Takao Omura, Enrique J. Cobos, Alban Latrémolière, Nader Ghasemlou, Gary J. Brenner, Ed van Veen, Lee Barrett, Tomokazu Sawada, Fuying Gao, Giovanni Coppola, Frank Gertler, Michael Costigan, Dan Geschwind, Clifford J. Woolf

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Figure 1

WGCNA and nearest neighbor analysis (NNA).

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WGCNA and nearest neighbor analysis (NNA). After building a WGCNA networ...
After building a WGCNA network on a microarray data set using multiple models of DRG injury, Hspb1 was used as a seed, and the 30 closest neighbors were identified using TO as a measure of connection strength. (A) Heat map depicting fold changes of the top 30 Hspb1 neighbors in several experimental models of DRG injury (demarcated by the color bar at the top), compared with the average expression in naive (N) samples (dark gray): spared nerve injury (SNI) (red), chronic nerve constriction (green), and spinal nerve ligation (SNL) (blue). Sham lesions are identified in light gray. Genes are clustered by similarity, with upregulated genes in red, and downregulated genes in green. Changes are expressed in log2 scale. CCI, chronic constriction injury. (B) Visualization of the top 30 nearest neighbors to Hspb1. Two connected genes have high TO and therefore share neighbors. Green gene symbols are those known to be involved in regeneration. Top connections of Hspb1 are depicted in red.