Tumor suppressor Nf2/merlin drives Schwann cell changes following electromagnetic field exposure through Hippo-dependent mechanisms

Abstract

Previous evidence showed mutations of the neurofibromin type 2 gene (Nf2), encoding the tumor suppressor protein merlin, in sporadic and vestibular schwannomas affecting Schwann cells (SCs). Accordingly, efforts have been addressed to identify possible factors, even environmental, that may regulate neurofibromas growth. In this context, we investigated the exposure of SC to an electromagnetic field (EMF), which is an environmental issue modulating biological processes. Here, we show that SC exposed to 50 Hz EMFs changes their morphology, proliferation, migration and myelinating capability. In these cells, merlin is downregulated, leading to activation of two intracellular signaling pathways, ERK/AKT and Hippo. Interestingly, SC changes their phenotype toward a proliferative/migrating state, which in principle may be pathologically relevant for schwannoma development.

Schwann Cell Autocrine and Paracrine Regulatory Mechanisms, Mediated by Allopregnanolone and BDNF, Modulate PKCε in Peripheral Sensory Neurons

“…At the third in vitro passage, SCs were treated for 48 h with 4 μM forskolin, then used for different assays. SC purity (more than 98%) was tested with a specific antibody against glycoprotein P0 [ 30 ]. Phase-contrast images of DRG neurons and SCs in vitro cultures are provided in Supplementary Figure S2…”

“…DRG neurons were characterized by immunofluorescence for neurofilament of 200 kDa (NF200, Sigma-Aldrich), as described [14,29]. SCs cultures were obtained as previously described [14,30]. Sciatic nerves were digested with 1% collagenase and 0.25% trypsin (Sigma-Aldrich), then mechanically dissociated, filtered through a 100 µm filter (BD Biosciences) and centrifuged 5 min at 900 rpm.…”

Influence of Mechanical Stimuli on Schwann Cell Biology

“…The most notables are YAP and TAZ, two transcriptional activators of the Hippo pathway. Indeed, several works have shown that YAP can be activated through the Hippo pathway in SCs by Crb/Amolt proteins (Colciago et al, 2015 ; Fernando et al, 2016 ). In addition, mechanical stimulation through a signaling cascade involving FAK, Src, PI3K, JNK pathways (Codelia et al, 2014 ; Mohseni et al, 2014 ; Kim and Gumbiner, 2015 ; Elbediwy et al, 2016 ), or formation of actomyosin filaments and presence of F-actin (Dupont et al, 2011 ; Aragona et al, 2013 ) can regulate YAP and TAZ.…”

“…Less studied, the stimulation of SCs by electromagnetic fields also opens interesting perspectives in peripheral nerve regeneration (Sisken et al, 1989 ; Kanje, 1992 ). Indeed, application of an electromagnetic field to cultured SCs promotes their proliferation and migration, presumably through YAP/TAZ (Colciago et al, 2015 ). Finally, physical therapy has also been considered as a therapeutic approach to stimulate tensile strain on peripheral nerves.…”

YAP and TAZ Regulate Cc2d1b and Purβ in Schwann Cells

“…Mechanical stimulation can regulate YAP/TAZ through signals involving FAK, Src, PI3K and JNK pathways (Codelia et al, 2014; Mohseni et al, 2014; Kim and Gumbiner, 2015; Elbediwy et al, 2016), or the formation of actomyosin filaments and accumulation of F-actin (Dupont et al, 2011; Aragona et al, 2013). In addition, YAP/TAZ in SCs can be activated through Crb/Amolt proteins and laminin/G-protein signaling (Colciago et al, 2015; Fernando et al, 2016; Poitelon et al, 2016; Deng et al, 2017). YAP/TAZ regulate gene expression by binding to other DNA-binding transcription factors, especially TEAD transcription factors, but also p73, ERBB4, EGR-1 SMADs RUNXs and TBX5 (Kim et al, 2018).…”