Dlg1-PTEN interaction regulates myelin thickness to prevent damaging peripheral nerve overmyelination.
The thickness of the myelin sheath that insulates axons is fitted for optimal nerve conduction velocity. Here, we show that, in Schwann cells, mammalian disks large homolog 1 (Dlg1) interacts with PTEN (phosphatase and tensin homolog deleted on chromosome 10) to inhibit axonal stimulation of myelination. This mechanism limits myelin sheath thickness and prevents overmyelination in mouse sciatic nerves. Removing this brake results also in myelin outfoldings and demyelination, characteristics of some peripheral neuropathies. Indeed, the Dlg1 brake is no longer functional in a mouse model of Charcot-Marie-Tooth disease. Therefore, negative regulation of myelination appears to be essential for optimization of nerve conduction velocity and myelin maintenance.
Cotter
Laurent
L
Institute of Cell Biology, Department of Biology, Eidgenössische Technische Hochschule (ETH) Zürich, CH-8093 Zürich, Switzerland.
Ozçelik
Murat
M
Jacob
Claire
C
Pereira
Jorge A
JA
Locher
Veronica
V
Baumann
Reto
R
Relvas
João B
JB
Suter
Ueli
U
Tricaud
Nicolas
N
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000502:physiology; D018920:Coculture Techniques; D000074288:Discs Large Homolog 1 Protein; D005727:Ganglia, Spinal / Q000166:cytology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000502:physiology* / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009431:Neural Conduction; D020890:Neuregulin-1 / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D000074407:SAP90-PSD95 Associated Proteins; D012583:Schwann Cells / Q000502:physiology*; D012584:Sciatic Nerve / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D000074288:Discs Large Homolog 1 Protein; C000614189:Dlg1 protein, mouse; C501119:Dlg1 protein, rat; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D000074407:SAP90-PSD95 Associated Proteins; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse