Abstract:Caspr/paranodin is an essential neuronal component of paranodal axoglial junctions, associated with contactin/F3. Its short intracellular domain contains a conserved motif (GNP motif) capable of binding protein 4.1 domains [FERM domains (four point one, ezrin, radixin, moesin)]. Schwannomin/merlin is a tumour suppressor expressed in many cell types, including in neurons, the function and partners of which are still poorly characterized. We show that the FERM domain of schwannomin binds to the paranodin GNP mot… Show more
“…In our initial screen of proteins that might anchor merlin to lipid rafts, we found that three putative merlin-binding proteins, CD44 (12,48),  1 integrin (49,50), and paxillin (51), were not required for merlin to be in lipid rafts. In fact, these three proteins were found to be Triton soluble in Optiprep gradients under the same conditions in which merlin was raft associated (data not shown).…”
Neurofibromatosis type 2 (NF2) is a genetic disorder characterized by bilateral schwannomas of the eighth cranial nerve. The NF2 tumor suppressor protein, merlin, is related to the ERM (ezrin, radixin, and moesin) family of membrane/F-actin linkers. Merlin resists solubilization by the detergent Triton X-100 (TX-100), a property commonly attributed to association with the cytoskeleton. Accordingly, NF2 patient mutations that encode merlins with enhanced TX-100 solubility have been explained previously in terms of loss of cytoskeletal attachment. However, here we present data to suggest that the detergent resistance of merlin is a result of its constitutive residence in lipid rafts. Furthermore, when cells are grown to high density, merlin shifts to a more buoyant lipid raft fraction in a density gradient. This shift is mimicked in subconfluent cells treated with cytochalasin D, suggesting that the shift results from merlin dissociation from the actin cytoskeleton, but not from lipid rafts. Intramolecular NH 2 -and COOH-terminal binding, which occurs when merlin transitions to the growth-suppressive form, also brings about a similar change in buoyant density. Our results suggest that constitutive residence of merlin in lipid rafts is crucial for its function and that as merlin becomes growth suppressive in vivo, one significant molecular event may be the loss of interaction with the actin cytoskeleton. To our knowledge, merlin is the first tumor suppressor known to reside within lipid rafts, and the significance of this finding is underscored by known loss-of-function NF2 patient mutations that encode merlins with enhanced TX-100 solubility.
“…In our initial screen of proteins that might anchor merlin to lipid rafts, we found that three putative merlin-binding proteins, CD44 (12,48),  1 integrin (49,50), and paxillin (51), were not required for merlin to be in lipid rafts. In fact, these three proteins were found to be Triton soluble in Optiprep gradients under the same conditions in which merlin was raft associated (data not shown).…”
Neurofibromatosis type 2 (NF2) is a genetic disorder characterized by bilateral schwannomas of the eighth cranial nerve. The NF2 tumor suppressor protein, merlin, is related to the ERM (ezrin, radixin, and moesin) family of membrane/F-actin linkers. Merlin resists solubilization by the detergent Triton X-100 (TX-100), a property commonly attributed to association with the cytoskeleton. Accordingly, NF2 patient mutations that encode merlins with enhanced TX-100 solubility have been explained previously in terms of loss of cytoskeletal attachment. However, here we present data to suggest that the detergent resistance of merlin is a result of its constitutive residence in lipid rafts. Furthermore, when cells are grown to high density, merlin shifts to a more buoyant lipid raft fraction in a density gradient. This shift is mimicked in subconfluent cells treated with cytochalasin D, suggesting that the shift results from merlin dissociation from the actin cytoskeleton, but not from lipid rafts. Intramolecular NH 2 -and COOH-terminal binding, which occurs when merlin transitions to the growth-suppressive form, also brings about a similar change in buoyant density. Our results suggest that constitutive residence of merlin in lipid rafts is crucial for its function and that as merlin becomes growth suppressive in vivo, one significant molecular event may be the loss of interaction with the actin cytoskeleton. To our knowledge, merlin is the first tumor suppressor known to reside within lipid rafts, and the significance of this finding is underscored by known loss-of-function NF2 patient mutations that encode merlins with enhanced TX-100 solubility.
“…Rabbit antibodies against paranodin (L51), Caspr2, and syndecan 4 have been described previously (Menegoz et al, 1997;Denisenko-Nehrbass et al, 2003;Goutebroze et al, 2003). The antineurofascin antibody reacting with NF155 and NF186 was generated by immunizing rabbits with the common intracellular region of the protein (residues 1065-1175; GenBank accession number AY061639) fused to glutathione S-transferase.…”
Section: Methodsmentioning
confidence: 99%
“…Schwannomin-like immunoreactivity has been reported in paranodal regions and SchmidtLanterman incisures (SLIs) (Scherer and Gutmann, 1996), which are cytoplasmic channels interrupting the compact myelin. In neurons, schwannomin can associate with the cytoplasmic tail of the paranodal protein paranodin/Caspr (Denisenko-Nehrbass et al, 2003), whereas in Schwann cells, it is localized to the plasma membrane through a paxillin-mediated interaction with 1-integrin (Obremski et al, 1998;Fernandez-Valle et al, 2002).…”
Schwannomin/merlin is the product of a tumor suppressor gene mutated in neurofibromatosis type 2 (NF2). Although the consequences of NF2 mutations on Schwann cell proliferation are well established, the physiological role of schwannomin in differentiated cells is not known. To unravel this role, we studied peripheral nerves in mice overexpressing in Schwann cells schwannomin with a deletion occurring in NF2 patients (P0 -SCH-⌬39 -121) or a C-terminal deletion. The myelin sheath and nodes of Ranvier were essentially preserved in both lines. In contrast, the ultrastructural and molecular organization of contacts between Schwann cells and axons in paranodal and juxtaparanodal regions were altered, with irregular juxtaposition of normal and abnormal areas of contact. Similar but more severe alterations were observed in mice with conditional deletion of the Nf2 gene in Schwann cells. The number of SchmidtLanterman incisures, which are cytoplasmic channels interrupting the compact myelin and characterized by distinct autotypic contacts, was increased in the three mutant lines. P0 -SCH-⌬39 -121 and conditionally deleted mice displayed exuberant wrapping of nonmyelinated fibers and short internodes, an abnormality possibly related to altered control of Schwann cell proliferation. In support of this hypothesis, Schwann cell number was increased along fibers before myelination in P0 -SCH-⌬39 -121 mice but not in those with C-terminal deletion. Schwann cell numbers were also more numerous in mice with conditional deletion. Thus, schwannomin plays an important role in the control of Schwann cell number and is necessary for the correct organization and regulation of axoglial heterotypic and glio-glial autotypic contacts.
“…For instance, N-terminal merlin can be associated with Caspr/paranodin, an axonal transmembrane glycoprotein enriched at paranodal junctions and important for the reciprocal axo-glial signaling [80]. Merlin also interacts with βII-spectrin - another molecule supporting the axonal cytoskeleton at paranodes (see Table 1) - essential for myelinated axon domain organization [30,49,81].…”
Section: The Hereditary Disease Neurofibromatosis Typementioning
confidence: 99%
“…In contrast to merlin isoform 2, which is specifically implicated in axon structure maintenance, both major merlin isoforms appear to have equal potency in affecting Nrg1 type III.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.…”
Section: The Hereditary Disease Neurofibromatosis Typementioning
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.
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