Axonal neuregulin 1 is a rate limiting but not essential factor for nerve remyelination

Florence R. Fricker; Ana Antunes-Martins; Jorge Galino Barres; Remi Paramsothy; Federica La Russa; James Perkins; Rebecca Goldberg; Jack Brelstaff; Ning Zhu; Stephen B. McMahon; Christine Orengo; Alistair N. Garratt; Carmen Birchmeier; David L H Bennett

doi:10.1093/brain/awt148

Axonal neuregulin 1 is a rate limiting but not essential factor for nerve remyelination

Florence R. Fricker, Ana Antunes-Martins, Jorge Galino Barres, Remi Paramsothy, Federica La Russa, James Perkins, Rebecca Goldberg, Jack Brelstaff, Ning Zhu, Stephen B. McMahon, Christine Orengo, Alistair N. Garratt, Carmen Birchmeier, David L H Bennett^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

74 Citations (Scopus)

Abstract

Neuregulin 1 acts as an axonal signal that regulates multiple aspects of Schwann cell development including the survival and migration of Schwann cell precursors, the ensheathment of axons and subsequent elaboration of the myelin sheath. To examine the role of this factor in remyelination and repair following nerve injury, we ablated neuregulin 1 in the adult nervous system using a tamoxifen inducible Cre recombinase transgenic mouse system. The loss of neuregulin 1 impaired remyelination after nerve crush, but did not affect Schwann cell proliferation associated with Wallerian degeneration or axon regeneration or the clearance of myelin debris by macrophages. Myelination changes were most marked at 10 days after injury but still apparent at 2 months post-crush. Transcriptional analysis demonstrated reduced expression of myelin-related genes during nerve repair in animals lacking neuregulin 1. We also studied repair over a prolonged time course in a more severe injury model, sciatic nerve transection and reanastamosis. In the neuregulin 1 mutant mice, remyelination was again impaired 2 months after nerve transection and reanastamosis. However, by 3 months post-injury axons lacking neuregulin 1 were effectively remyelinated and virtually indistinguishable from control. Neuregulin 1 signalling is therefore an important factor in nerve repair regulating the rate of remyelination and functional recovery at early phases following injury. In contrast to development, however, the determination of myelination fate following nerve injury is not dependent on axonal neuregulin 1 expression. In the early phase following injury, axonal neuregulin 1 therefore promotes nerve repair, but at late stages other signalling pathways appear to compensate.

Original language	English
Pages (from-to)	2279-2297
Number of pages	19
Journal	Brain : a journal of neurology
Volume	136
Issue number	7
DOIs	https://doi.org/10.1093/brain/awt148
Publication status	Published - Jul 2013

Keywords

injury
Nrg1
regeneration
remyelination
Schwann

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Fricker, F. R., Antunes-Martins, A., Galino Barres, J., Paramsothy, R., La Russa, F., Perkins, J., Goldberg, R., Brelstaff, J., Zhu, N., McMahon, S. B., Orengo, C., Garratt, A. N., Birchmeier, C., & Bennett, D. L. H. (2013). Axonal neuregulin 1 is a rate limiting but not essential factor for nerve remyelination. Brain : a journal of neurology, 136(7), 2279-2297. https://doi.org/10.1093/brain/awt148

@article{4e8a2e14f73c486f8c2f81e232b7ee31,

title = "Axonal neuregulin 1 is a rate limiting but not essential factor for nerve remyelination",

abstract = "Neuregulin 1 acts as an axonal signal that regulates multiple aspects of Schwann cell development including the survival and migration of Schwann cell precursors, the ensheathment of axons and subsequent elaboration of the myelin sheath. To examine the role of this factor in remyelination and repair following nerve injury, we ablated neuregulin 1 in the adult nervous system using a tamoxifen inducible Cre recombinase transgenic mouse system. The loss of neuregulin 1 impaired remyelination after nerve crush, but did not affect Schwann cell proliferation associated with Wallerian degeneration or axon regeneration or the clearance of myelin debris by macrophages. Myelination changes were most marked at 10 days after injury but still apparent at 2 months post-crush. Transcriptional analysis demonstrated reduced expression of myelin-related genes during nerve repair in animals lacking neuregulin 1. We also studied repair over a prolonged time course in a more severe injury model, sciatic nerve transection and reanastamosis. In the neuregulin 1 mutant mice, remyelination was again impaired 2 months after nerve transection and reanastamosis. However, by 3 months post-injury axons lacking neuregulin 1 were effectively remyelinated and virtually indistinguishable from control. Neuregulin 1 signalling is therefore an important factor in nerve repair regulating the rate of remyelination and functional recovery at early phases following injury. In contrast to development, however, the determination of myelination fate following nerve injury is not dependent on axonal neuregulin 1 expression. In the early phase following injury, axonal neuregulin 1 therefore promotes nerve repair, but at late stages other signalling pathways appear to compensate. ",

keywords = "injury, Nrg1, regeneration, remyelination, Schwann",

author = "Fricker, {Florence R.} and Ana Antunes-Martins and {Galino Barres}, Jorge and Remi Paramsothy and {La Russa}, Federica and James Perkins and Rebecca Goldberg and Jack Brelstaff and Ning Zhu and McMahon, {Stephen B.} and Christine Orengo and Garratt, {Alistair N.} and Carmen Birchmeier and Bennett, {David L H}",

year = "2013",

month = jul,

doi = "10.1093/brain/awt148",

language = "English",

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Fricker, FR, Antunes-Martins, A , Galino Barres, J, Paramsothy, R, La Russa, F, Perkins, J, Goldberg, R, Brelstaff, J, Zhu, N, McMahon, SB, Orengo, C, Garratt, AN, Birchmeier, C & Bennett, DLH 2013, 'Axonal neuregulin 1 is a rate limiting but not essential factor for nerve remyelination', Brain : a journal of neurology, vol. 136, no. 7, pp. 2279-2297. https://doi.org/10.1093/brain/awt148

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T1 - Axonal neuregulin 1 is a rate limiting but not essential factor for nerve remyelination

AU - Fricker, Florence R.

AU - Antunes-Martins, Ana

AU - Galino Barres, Jorge

AU - Paramsothy, Remi

AU - La Russa, Federica

AU - Perkins, James

AU - Goldberg, Rebecca

AU - Brelstaff, Jack

AU - Zhu, Ning

AU - McMahon, Stephen B.

AU - Orengo, Christine

AU - Garratt, Alistair N.

AU - Birchmeier, Carmen

AU - Bennett, David L H

PY - 2013/7

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N2 - Neuregulin 1 acts as an axonal signal that regulates multiple aspects of Schwann cell development including the survival and migration of Schwann cell precursors, the ensheathment of axons and subsequent elaboration of the myelin sheath. To examine the role of this factor in remyelination and repair following nerve injury, we ablated neuregulin 1 in the adult nervous system using a tamoxifen inducible Cre recombinase transgenic mouse system. The loss of neuregulin 1 impaired remyelination after nerve crush, but did not affect Schwann cell proliferation associated with Wallerian degeneration or axon regeneration or the clearance of myelin debris by macrophages. Myelination changes were most marked at 10 days after injury but still apparent at 2 months post-crush. Transcriptional analysis demonstrated reduced expression of myelin-related genes during nerve repair in animals lacking neuregulin 1. We also studied repair over a prolonged time course in a more severe injury model, sciatic nerve transection and reanastamosis. In the neuregulin 1 mutant mice, remyelination was again impaired 2 months after nerve transection and reanastamosis. However, by 3 months post-injury axons lacking neuregulin 1 were effectively remyelinated and virtually indistinguishable from control. Neuregulin 1 signalling is therefore an important factor in nerve repair regulating the rate of remyelination and functional recovery at early phases following injury. In contrast to development, however, the determination of myelination fate following nerve injury is not dependent on axonal neuregulin 1 expression. In the early phase following injury, axonal neuregulin 1 therefore promotes nerve repair, but at late stages other signalling pathways appear to compensate.

AB - Neuregulin 1 acts as an axonal signal that regulates multiple aspects of Schwann cell development including the survival and migration of Schwann cell precursors, the ensheathment of axons and subsequent elaboration of the myelin sheath. To examine the role of this factor in remyelination and repair following nerve injury, we ablated neuregulin 1 in the adult nervous system using a tamoxifen inducible Cre recombinase transgenic mouse system. The loss of neuregulin 1 impaired remyelination after nerve crush, but did not affect Schwann cell proliferation associated with Wallerian degeneration or axon regeneration or the clearance of myelin debris by macrophages. Myelination changes were most marked at 10 days after injury but still apparent at 2 months post-crush. Transcriptional analysis demonstrated reduced expression of myelin-related genes during nerve repair in animals lacking neuregulin 1. We also studied repair over a prolonged time course in a more severe injury model, sciatic nerve transection and reanastamosis. In the neuregulin 1 mutant mice, remyelination was again impaired 2 months after nerve transection and reanastamosis. However, by 3 months post-injury axons lacking neuregulin 1 were effectively remyelinated and virtually indistinguishable from control. Neuregulin 1 signalling is therefore an important factor in nerve repair regulating the rate of remyelination and functional recovery at early phases following injury. In contrast to development, however, the determination of myelination fate following nerve injury is not dependent on axonal neuregulin 1 expression. In the early phase following injury, axonal neuregulin 1 therefore promotes nerve repair, but at late stages other signalling pathways appear to compensate.

KW - injury

KW - Nrg1

KW - regeneration

KW - remyelination

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JO - Brain : a journal of neurology

JF - Brain : a journal of neurology

IS - 7

ER -

Axonal neuregulin 1 is a rate limiting but not essential factor for nerve remyelination

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Keywords

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