CMT 4B1: membrane homeostasis in schwann cell myelination

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J Neurosci. 2009 Jul 8;29(27):8858-70.

Dlg1, Sec8, and Mtmr2 regulate membrane homeostasis in schwann cell myelination.

Bolis A, Coviello S, Visigalli I, Taveggia C, Bachi A, Chishti AH, Hanada T,

Quattrini A, Previtali SC, Biffi A, Bolino A.

Dulbecco Telethon Institute, San Raffaele Scientific Institute, 20132 Milan,

Italy.

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.