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A Neuronal Function of the Tumor Suppressor Protein Merlin


A Neuronal Function of the Tumor Suppressor Protein Merlin

Alexander Schulz et al. Acta Neuropathol Commun.


Mutagenic loss of the NF2 tumor suppressor gene encoded protein merlin is known to provoke the hereditary neoplasia syndrome, Neurofibromatosis type 2 (NF2). In addition to glial cell-derived tumors in the PNS and CNS, disease-related lesions also affect the skin and the eyes. Furthermore, 60% of NF2 patients suffer from peripheral nerve damage, clinically referred to as peripheral neuropathy. Strikingly, NF2-associated neuropathy often occurs in the absence of nerve damaging tumors, suggesting tumor-independent events. Recent findings indicate an important role of merlin in neuronal cell types concerning neuromorphogenesis, axon structure maintenance and communication between axons and Schwann cells. In this review, we compile clinical and experimental evidences for the underestimated role of the tumor suppressor merlin in the neuronal compartment.


Figure 1
Figure 1
Potential role for merlin isoform 2 in NF2-related neuropathy. Merlin isoform 2 in axons assembles a multi-protein complex with RhoGDI [68] and RhoGAP that leads to the local activation of the small GTPase RhoA by GTP loading [45]. This results in subsequent neurofilament phosphorylation through Rho-associated kinase (ROCK). The specific loss of merlin isoform 2 can therefore provoke irregular neurofilament phosphorylation and impaired axon structure maintenance.
Figure 2
Figure 2
Interaction of neuronally expressed merlin with axonal proteins essential for axon-Schwann cell signaling. Merlin in neurons has been shown to interact with two axonal proteins in the paranode region of myelinated axons: Caspr/paranodin [80] and βII-spectrin [30]. Furthermore, merlin regulates the expression of Nrg1 type III [85], an axon surface molecule with growth factor-like impact on Schwann cell behavior. Interestingly, the receptor of Nrg1 type III on Schwann cells, ErBB2/3 [33] as well as its co-receptor CD44 [14], is regulated by merlin expressed in Schwann cells.

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