Neuronal merlin influences ERBB2 receptor expression on Schwann cells through neuregulin 1 type III signalling

Schulz, Alexander; Kyselyova, Anna A.; Baader, Stephan L.; Jung, Marie Juliane; Zoch, Ansgar; Mautner, Victor‐Felix; Hagel, Christian; Morrison, Helen

doi:10.1093/brain/awt327

Cited by 31 publications

(37 citation statements)

References 33 publications

(48 reference statements)

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“…As noted above, merlin regulates the expressio n, subcellular localization, and activity of RTKs, including ErbB2 and PDGFR (Fraenzer et al, 2003; Brown and Hansen, 2008; Lallemand et al, 2009b; Schulz et al, 2014). It likewise suppresses the activity of several downstream pro-growth signaling cascades including Ras, Rac1/Cdc42, Raf, PAK1/2, extracellular regulated kinase/mitogen activated protein kinase (ERK/MAPK), phosphatidyl-inositol 3-kinase (PI3-K)/Akt/mTORC, and JNK (Guo et al, 2012; Zhou and Hanemann, 2012).…”

Section: Discussionmentioning

confidence: 95%

Merlin status regulates p75NTR expression and apoptotic signaling in Schwann cells following nerve injury

Ahmad

Fernando

Gurgel

et al. 2015

Neurobiology of Disease

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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, p75NTR. Merlin is the protein product of the NF2 tumor suppressor gene implicated in SC tumorigenesis. Here we explore the contribution of merlin to SCs 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 p75NTR expression. p75NTR levels are elevated in P0SchΔ39-121 transgenic mice that harbor a 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 phosphomimetic (S518D), merlin isoforms suppresses p75NTR expression in primary human schwannoma cultures which otherwise lack functional merlin. Despite elevated levels of p75NTR, 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 p75NTR-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 p75NTR expression. Further, they demonstrate that merlin facilitates p75NTR-mediated apoptosis in SCs helping to explain how neoplastic SCs that lack functional merlin survive long-term in the absence of axonal contact.

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Section: Discussionmentioning

confidence: 95%

Merlin status regulates p75NTR expression and apoptotic signaling in Schwann cells following nerve injury

Ahmad

Fernando

Gurgel

et al. 2015

Neurobiology of Disease

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“…42 In relation to this, loss or diminution of merlin in peripheral nerve fibers that may cause the neuropathy in NF2 patients independent of the presence of Schwann cell tumors has been described. [43][44][45] The authors discussed an important role of merlin in neuronal cell types with regard to neuromorphogenesis, axon structure maintenance, and communication between axons and Schwann cells. Therefore, it is possible that NF2-related neuropathy has a multifactorial origin (as commented on by Morrison in the study by Plotkin et al 46 .…”

Section: Discussionmentioning

confidence: 99%

Muscle action potential scans and ultrasound imaging in neurofibromatosis type 2

et al. 2016

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“…A major unresolved question is how the rate of neuronal Nrg1 expression is regulated in the first place, i.e. as a function of axon caliber and length, and how axonal Nrg1 TypeIII affects expression of the glial Erbb gene itself (Schulz et al, 2014) and thus Schwann cell responsiveness.…”

Section: Myelination Of Axonal Processesmentioning

confidence: 99%

Neuregulin-ERBB Signaling in the Nervous System and Neuropsychiatric Diseases

Mei

Nave

2014

Neuron

475

425

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Summary Neuregulins (NRGs) comprise a large family of growth factors that stimulate ERBB receptor tyrosine kinases. NRGs and their receptors ERBBs have been identified as susceptibility genes for diseases such as schizophrenia (SZ) and bipolar disorder. Recent studies have revealed complex Nrg/Erbb signaling networks that regulate the assembly of neural circuitry, myelination, neurotransmission and synaptic plasticity. Evidence indicates there is an optimal level of NRG/ERBB signaling in the brain and deviation from it impairs brain functions. NRGs/ERBBs and downstream signaling pathways may provide therapeutic targets for specific neuropsychiatric symptoms.

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Neuronal merlin influences ERBB2 receptor expression on Schwann cells through neuregulin 1 type III signalling

Cited by 31 publications

References 33 publications

Merlin status regulates p75NTR expression and apoptotic signaling in Schwann cells following nerve injury

Merlin status regulates p75NTR expression and apoptotic signaling in Schwann cells following nerve injury

Muscle action potential scans and ultrasound imaging in neurofibromatosis type 2

Neuregulin-ERBB Signaling in the Nervous System and Neuropsychiatric Diseases

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