Merlin status regulates p75(NTR) expression and apoptotic signaling in Schwann cells following nerve injury

Iram Ahmad; Augusta Fernando; Richard Gurgel; J. Jason Clark; Linjing Xu; Marlan R Hansen

doi:10.1016/j.nbd.2015.05.021

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Merlin status regulates p75(NTR) expression and apoptotic signaling in Schwann cells following nerve injury

Journal article

Peer reviewed

Merlin status regulates p75(NTR) expression and apoptotic signaling in Schwann cells following nerve injury

Iram Ahmad, Augusta Fernando, Richard Gurgel, J. Jason Clark, Linjing Xu and Marlan R Hansen

Neurobiology of disease, Vol.82, pp.114-122

10/2015

DOI: 10.1016/j.nbd.2015.05.021

PMCID: PMC4641051

PMID: 26057084

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https://doaj.org/article/2e793da451144fdebc0ec94d7a978441View

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Abstract

After nerve injury, Schwann cells (SCs) dedifferentiate, proliferate, and support axon regrowth. If axons fail to regenerate, denervated SCs eventually undergo apoptosis due, in part, to increased expression of the low-affinity neurotrophin receptor, p75(NTR). Merlin is the protein product of the NF2 tumor suppressor gene implicated in SC tumorigenesis. Here we explore the contribution of merlin to SC responses to nerve injury. We find that merlin becomes phosphorylated (growth permissive) in SCs following acute axotomy and following gradual neural degeneration in a deafness model, temporally correlated with increased p75(NTR) expression. p75(NTR) levels are elevated in P0SchΔ39-121 transgenic mice that harbor an Nf2 mutation in SCs relative to wild-type mice before axotomy and remain elevated for a longer period of time following injury. Replacement of wild-type, but not phospho-mimetic (S518D), merlin isoforms suppresses p75(NTR) expression in primary human schwannoma cultures which otherwise lack functional merlin. Despite elevated levels of p75(NTR), SC apoptosis following axotomy is blunted in P0SchΔ39-121 mice relative to wild-type mice suggesting that loss of functional merlin contributes to SC resistance to apoptosis. Further, cultured SCs from mice with a tamoxifen-inducible knock-out of Nf2 confirm that SCs lacking functional merlin are less sensitive to p75(NTR)-mediated cell death. Taken together these results point to a model whereby loss of axonal contact following nerve injury results in merlin phosphorylation leading to increased p75(NTR) expression. Further, they demonstrate that merlin facilitates p75(NTR)-mediated apoptosis in SCs helping to explain how neoplastic SCs that lack functional merlin survive long-term in the absence of axonal contact.

Cell Dedifferentiation - physiology

Cell Proliferation

Humans

Nerve Regeneration - physiology

Cells, Cultured

Peripheral Nerve Injuries - pathology

Axons - metabolism

Mice, Transgenic

Schwann Cells - pathology

Schwann Cells - metabolism

Rats, Sprague-Dawley

Axotomy

Animals

Peripheral Nerve Injuries - metabolism

Axons - pathology

Neuroma, Acoustic - pathology

Signal Transduction - physiology

Mice

Neuroma, Acoustic - metabolism

Apoptosis - physiology

Neurofibromin 2 - metabolism

Receptor, Nerve Growth Factor - metabolism

Details

Title: Subtitle: Merlin status regulates p75(NTR) expression and apoptotic signaling in Schwann cells following nerve injury
Creators: Iram Ahmad - Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, USA
Augusta Fernando - Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, USA
Richard Gurgel - Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, USA
J. Jason Clark - Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, USA
Linjing Xu - Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, USA
Marlan R Hansen - Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, USA; Department of Neurosurgery, University of Iowa, Iowa City, IA 52242, USA. Electronic address: marlan-hansen@uiowa.edu
Resource Type: Journal article
Publication Details: Neurobiology of disease, Vol.82, pp.114-122
DOI: 10.1016/j.nbd.2015.05.021
PMID: 26057084
PMCID: PMC4641051
NLM abbreviation: Neurobiol Dis
ISSN: 0969-9961
eISSN: 1095-953X
Publisher: United States
Grant note: R01DC009801 / NIDCD NIH HHS T32 DC000040 / NIDCD NIH HHS R01 DC009801 / NIDCD NIH HHS P30DC010362 / NIDCD NIH HHS P30 DC010362 / NIDCD NIH HHS T32DC000040 / NIDCD NIH HHS
Language: English
Date published: 10/2015
Academic Unit: Molecular Physiology and Biophysics; Neurosurgery; Otolaryngology
Record Identifier: 9984006460902771

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