Sustained activation of ERK1/2 MAPK in Schwann cells causes corneal neurofibroma

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RAS‐mitogen activated kinase (RAS‐MAPK) signaling is a major pathway for the transmission of a broad range of growth factors and extracellular signals that affect such cellular processes as proliferation, migration, and the cell cycle (Rauen, 2013). The key effector kinases of this pathway are extracellular signal‐regulated kinases 1 and 2 (ERK1/2), which are activated by mitogen kinase kinase 1 (MEK1; Brunet et al., 1999; Fey, Matallanas, Rauch, Rukhlenko, & Kholodenko, 2016). Recently, it was shown that myelin thickness increases in the central nervous system (CNS) and peripheral nervous system (PNS) when ERK1/2 activity was modestly elevated in oligodendrocytes and Schwann cells of heterozygous transgenic mice through constitutive expression of Mek1 (CnpCre;MekDD/+ [Ishii, Furusho, & Bansal, 2013]). These findings suggest that ERK1/2 plays a key role in the maintenance of the integrity of myelin and axons throughout adulthood (Ishii, Furusho, Dupree, & Bansal, 2014).
Thus, while controlling ERK1/2 activation can potentially have therapeutic effects in restoring normal myelin thickness and improving axonal survival in human demyelinating diseases (Ishii et al., 2014), this approach faces many challenges, because various cellular responses depend on the strength, duration, and timing of ERK1/2 activation (Dikic, Schlessinger, & Lax, 1994; Ebisuya, Kondoh, & Nishida, 2005; Katz, Amit, & Yarden, 2007). In this regard, hyperactivation of ERK1/2 in oligodendrocytes and SCs in the homozygous CnpCre;MekDD/MekDD transgenic line leads to progressive neurological deficits, accompanied by dysregulation of myelination, and axonal degeneration in the sciatic nerve and spinal cord (Ishii, Furusho, Dupree, & Bansal, 2016). Notably, both the heterozygous (Ishii et al., 2013) and homozygous (Ishii et al., 2016) transgenic mouse lines developed severe abnormalities in the eye, characterized by postnatal proptosis, and revealed opacification of the cornea.
The transparent cornea is a specialized tissue that is innervated by non‐myelinated axons that are adapted to serve its unique light refractive and sensory functions (Shaheen, Bakir, & Jain, 2014; Muller, Marfurt, Kruse, & Tervo, 2003; Belmonte, Acosta, & Gallar, 2004). These corneal axons arise from myelinated peripheral limbal fibers that enter the posterior corneal stroma, where they lose their perineurium and myelin sheaths. In mice, the corneal nerves are remodeled postnatally between 1 and 1.5 months (M), reaching maturity by 2 M following an increase in the cornea with age (He & Bazan, 2015). Corneal axons are ensheathed by non‐myelinating SCs (nmSCs) that form Remak bundles (Muller et al., 2003). Stromal keratocytes also lie near nerve bundles and occasionally wrap axons through cytoplasmic extensions (Muller, Vrensen, Pels, Cardozo, & Willekens, 1997).
Just as SCs provide trophic support to axons (reviewed in: Mirsky, Parmantier, McMahon, & Jessen, 1999), stromal keratocytes, through a similar trophic interdependent mechanism with axons, might also govern corneal homeostasis (reviewed in: Shaheen et al., 2014), which has significance in pathological situations, such as after injury and tumorigenesis (Zheng et al., 2008; Ribeiro et al., 2013). In this respect, injury to the cornea promotes keratocyte differentiation into wound fibroblasts, which develop further into contractile myofibroblasts, as a functional adaptation to support tissue repair via cell proliferation and cell migration (Fini & Stramer, 2005). The type III intermediate filament (IF) protein vimentin is pivotal in this process, aiding in mechanosensory activities through its upregulation (Bargagna‐Mohan et al., 2012; Gregor et al., 2014; Herrmann, Bar, Kreplak, Strelkov, & Aebi, 2007).
Phosphorylation of vimentin effects dynamic changes in the cytoskeletal structure through depolymerization of its filamentous form into soluble vimentin (sVim) for various functions, including cell signaling (Eriksson et al., 2004; Helfand, Chou, Shumaker, & Goldman, 2005; Cogli, Progida, Bramato, & Bucci, 2013; Robert, Hookway, & Gelfand, 2016).
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