title: Merlin status regulates p75(NTR) expression and apoptotic signaling in Schwann cells following nerve injury.
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.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Iram
authors.initials: I
authors.lastname: Ahmad
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Augusta
authors.initials: A
authors.lastname: Fernando
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Gurgel
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: J
authors.initials: J
authors.lastname: Jason Clark
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Linjing
authors.initials: L
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Marlan R
authors.initials: MR
authors.lastname: Hansen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001369:Axons / Q000378:metabolism / Q000473:pathology; D019771:Axotomy; D054337:Cell Dedifferentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000502:physiology; D025581:Neurofibromin 2 / Q000378:metabolism*; D009464:Neuroma, Acoustic / Q000378:metabolism / Q000473:pathology; D059348:Peripheral Nerve Injuries / Q000378:metabolism* / Q000473:pathology; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism*; D012583:Schwann Cells / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D025581:Neurofibromin 2; D020800:Receptor, Nerve Growth Factor
keywords: Axotomy; Cell death; Nerve growth factor; Neurofibromatosis type 2; Receptor; Schwann cells