Tumor Suppressor Schwannomin/Merlin Is Critical for the Organization of Schwann Cell Contacts in Peripheral Nerves

Abstract

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.

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

“…Interestingly, EdU-uptake was not significantly greater in normal, uninjured SCs from P0SchΔ39-121 mice compared with wild-type mice suggesting that loss of merlin function alone is not sufficient to drive peripheral nerve SCs into a significant hyperplastic response. Indeed, immmunolabeling and ultrastructural studies identified myelination abnormalities in sciatic nerves from P0SchΔ39-121 mice but did not reveal significant SC hyperplasia within the peripheral nerve (Denisenko et al, 2008). Rather, SC hyperplasia in P0SchΔ39-121 mice is found in foci near or within sensory ganglia and skeletal muscle (Giovannini et al, 2014), consistent with the observation that most schwannomas arise within sensory ganglia (Tryggvason et al, 2012), and suggesting that intraganglionic SCs are particularly sensitive to merlin status.…”

Identification of genes expressed by zebrafish oligodendrocytes using a differential microarray screen

“…Ppp1r14a can promote tumorigenesis by regulating activity of the Nf2/ Merlin tumor suppressor by means of myosin phosphatase (Jin et al, 2006). Nf2/Merlin has been implicated in control of Schwann cell number and organization of Schwann cell contact with axons (Scherer et al, 2001;Denisenko et al, 2008), but a function has not been described for oligodendrocytes. MID1 interacting protein 1b (mid1-ip1b, RefSeq:NM_200832, probe set Dr.25285.1.S1) is expressed by both oligodendrocytes (Figs.…”

Signals to promote myelin formation and repair

“…Merlin is encoded by the tumor suppressor gene NF2 (implicated in neurofibromatosis type 2 tumors) and is important for the formation of axon–glial junctions174…”