Expression of ATF3 and axonal outgrowth are impaired after delayed nerve repair.

Harukazu Saito,Lars B Dahlin

doi:10.1186/1471-2202-9-88

Abstract

BackgroundA delay in surgical nerve repair results in impaired nerve function in humans, but mechanisms behind the weakened nerve regeneration are not known. Activating transcription factor 3 (ATF3) increases the intrinsic growth state of injured neurons early after injury, but the role of long-term changes and their relation to axonal outgrowth after a delayed nerve repair are not well understood. ATF3 expression was examined by immunohistochemistry in motor and sensory neurons and in Schwann cells in rat sciatic nerve and related to axonal outgrowth after transection and delayed nerve repair (repair 0, 30, 90 or 180 days post-injury). Expression of the neuronal cell adhesion molecule (NCAM), which is expressed in non-myelinating Schwann cells, was also examined.ResultsThe number of neurons and Schwann cells expressing ATF3 declined and the length of axonal outgrowth was impaired if the repair was delayed. The decline was more rapid in motor neurons than in sensory neurons and Schwann cells. Regeneration distances over time correlated to number of ATF3 stained neurons and Schwann cells. Many neurofilament stained axons grew along ATF3 stained Schwann cells. If nerve repair was delayed the majority of Schwann cells in the distal nerve segment stained for NCAM.ConclusionDelayed nerve repair impairs nerve regeneration and length of axonal outgrowth correlates to ATF3 expression in both neurons and Schwann cells. Mainly non-myelinating Schwann cells (NCAM stained) are present in distal nerve segments after delayed nerve repair. These data provide a neurobiological basis for the poor outcomes associated with delayed nerve repair. Nerve trunks should, if possible, be promptly repaired.

Highlights

A delay in surgical nerve repair results in impaired nerve function in humans, but mechanisms behind the weakened nerve regeneration are not known
A significantly (Mann-Whitney; p < 0.005) higher number of Activating transcription factor 3 (ATF3) stained neurons and Schwann cells were present on the experimental side compared to contralateral, noninjured, side at all time points except: 1) number of ATF3 stained Schwann cells in the segment 15 mm proximal to the lesion were not different; 2) number of motor neurons in the groups where the sciatic nerve was repaired with a delay of 90 and 180 days
Sensory and motor neurons [13] and non-neuronal cells (i.e. Schwann cells; [14]) in the injured nerve trunk showed a decline in ATF3 response after transection and delayed nerve repair

Summary

Introduction

A delay in surgical nerve repair results in impaired nerve function in humans, but mechanisms behind the weakened nerve regeneration are not known. Activating transcription factor 3 (ATF3) increases the intrinsic growth state of injured neurons early after injury, but the role of long-term changes and their relation to axonal outgrowth after a delayed nerve repair are not well understood. ATF3 expression was examined by immunohistochemistry in motor and sensory neurons and in Schwann cells in rat sciatic nerve and related to axonal outgrowth after transection and delayed nerve repair (repair 0, 30, 90 or 180 days post-injury). Impaired nerve regeneration and weakened target reinnervation are significant clinical problems after nerve injury when the repair of a nerve trunk is delayed [1,2,3]. Detailed signal transduction mechanisms underlying the impaired nerve regeneration are not well understood

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