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The Journal of Neuroscience, October 15, 2008, 28(42):10472-10481; doi:10.1523/JNEUROSCI.2537-08.2008

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

Natalia Denisenko,^1,2,3 * Carmen Cifuentes-Diaz,^1,2,3 * Theano Irinopoulou,^1,2,3 Michèle Carnaud,^1,2,3 Evelyne Benoit,⁴ Michiko Niwa-Kawakita,^5,6 Fabrice Chareyre,^5,6 Marco Giovannini,^5,6 Jean-Antoine Girault,^1,2,3 and Laurence Goutebroze^1,2,3

¹Inserm, Unité Mixte de Recherche en Santé 839, Paris, 75005, France, ²Université Pierre et Marie Curie–Paris 6, Paris, 75005, France, ³Institut du Fer à Moulin, Paris, 75005, France, ⁴Centre National de la Recherche Scientifique, Institut de Neurobiologie Alfred Fessard, Laboratoire de Neurobiologie Cellulaire et Moléculaire, Unité Propre de Recherche 9040, Gif sur Yvette, 91198, France, ⁵Inserm, Unité 674, Paris, 75010, France, and ⁶Université Paris 7–Denis Diderot, Institut Universitaire d'Hématologie, Paris, 75010, France

Correspondence should be addressed to Jean-Antoine Girault, Inserm, Unité Mixte de Recherche en Santé 839, Institut du Fer à Moulin, 17 rue du Fer à Moulin, Paris, 75005, France. Email: jean-antoine.girault{at}inserm.fr

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 Schmidt–Lanterman 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.

Key words: neurofibromatosis type 2; nodes of Ranvier; paranodes; juxtaparanodes; Schmidt–Lanterman incisures; internodes

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Received June 2, 2008; revised Aug. 1, 2008; accepted Aug. 10, 2008.

Correspondence should be addressed to Jean-Antoine Girault, Inserm, Unité Mixte de Recherche en Santé 839, Institut du Fer à Moulin, 17 rue du Fer à Moulin, Paris, 75005, France. Email: jean-antoine.girault{at}inserm.fr

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