title: Dlg1, Sec8, and Mtmr2 regulate membrane homeostasis in Schwann cell myelination.
abstract: 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.
authors: Dulbecco Telethon Institute, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors: Annalisa
authors: A
authors: Bolis
authors: Silvia
authors: S
authors: Coviello
authors: Ilaria
authors: I
authors: Visigalli
authors: Carla
authors: C
authors: Taveggia
authors: Angela
authors: A
authors: Bachi
authors: Athar H
authors: AH
authors: Chishti
authors: Toshihiko
authors: T
authors: Hanada
authors: Angelo
authors: A
authors: Quattrini
authors: Stefano Carlo
authors: SC
authors: Previtali
authors: Alessandra
authors: A
authors: Biffi
authors: Alessandra
authors: A
authors: Bolino
mesh_terms: D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D002462:Cell Membrane / Q000502:physiology*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D018920:Coculture Techniques; D000074288:Discs Large Homolog 1 Protein; D015536:Down-Regulation / Q000502:physiology; D005089:Exocytosis / Q000502:physiology; D006367:HeLa Cells; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000502:physiology*; D009413:Nerve Fibers, Myelinated / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D000074407:SAP90-PSD95 Associated Proteins; D012583:Schwann Cells / Q000166:cytology / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D000074288:Discs Large Homolog 1 Protein; C000614189:Dlg1 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000074407:SAP90-PSD95 Associated Proteins; C489608:Sec8l1 protein, mouse; C498717:Mtmr2 protein, mouse; D054558:Protein Tyrosine Phosphatases, Non-Receptor