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The Journal of Neuroscience, July 8, 2009, 29(27):8858-8870; doi:10.1523/JNEUROSCI.1423-09.2009

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Neurobiology of Disease
Dlg1, Sec8, and Mtmr2 Regulate Membrane Homeostasis in Schwann Cell Myelination

Annalisa Bolis,^1,2 Silvia Coviello,^1,2 Ilaria Visigalli,³ Carla Taveggia,² Angela Bachi,⁴ Athar H. Chishti,⁵ Toshihiko Hanada,⁵ Angelo Quattrini,² Stefano Carlo Previtali,² Alessandra Biffi,³ and Alessandra Bolino^1,2

¹Dulbecco Telethon Institute, ²INSPE–Institute of Experimental Neurology, ³San Raffaele Telethon Institute for Gene Therapy, and ⁴Biological Mass Spectrometry, San Raffaele Scientific Institute, 20132 Milan, Italy, and ⁵Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois 60612

Correspondence should be addressed to Dr. Alessandra Bolino, Dulbecco Telethon Institute and INSPE–Institute of Experimental Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy. Email: bolino.alessandra{at}hsr.it

How membrane biosynthesis and homeostasis is achieved in myelinating glia is mostly unknown. We previously reported that loss of myotubularin-related protein 2 (MTMR2) provokes autosomal recessive demyelinating Charcot–Marie–Tooth type 4B1 neuropathy, characterized by excessive redundant myelin, also known as myelin outfoldings. We generated a Mtmr2-null mouse that models the human neuropathy. We also found that, in Schwann cells, Mtmr2 interacts with Discs large 1 (Dlg1), a scaffold involved in polarized trafficking and membrane addition, whose localization in Mtmr2-null nerves is altered. We here report that, in Schwann cells, Dlg1 also interacts with kinesin 13B (kif13B) and Sec8, which are involved in vesicle transport and membrane tethering in polarized cells, respectively. Taking advantage of the Mtmr2-null mouse as a model of impaired membrane formation, we provide here the first evidence for a machinery that titrates membrane formation during myelination. We established Schwann cell/DRG neuron cocultures from Mtmr2-null mice, in which myelin outfoldings were reproduced and almost completely rescued by Mtmr2 replacement. By exploiting this in vitro model, we propose a mechanism whereby kif13B kinesin transports Dlg1 to sites of membrane remodeling where it coordinates a homeostatic control of myelination. The interaction of Dlg1 with the Sec8 exocyst component promotes membrane addition, whereas with Mtmr2, negatively regulates membrane formation. Myelin outfoldings thus arise as a consequence of the loss of negative control on the amount of membrane, which is produced during myelination.

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Received March 25, 2009; revised May 20, 2009; accepted June 1, 2009.

Correspondence should be addressed to Dr. Alessandra Bolino, Dulbecco Telethon Institute and INSPE–Institute of Experimental Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy. Email: bolino.alessandra{at}hsr.it

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