SH3TC2, a protein mutant in CMT neuropathy, links peripheral nerve myelination t

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Brain. 2010 Aug;133(Pt 8):2462-74.

SH3TC2, a protein mutant in Charcot-Marie-Tooth neuropathy, links peripheral

nerve myelination to endosomal recycling.

Stendel C, Roos A, Kleine H, Arnaud E, Ozçelik M, Sidiropoulos PN, Zenker J,

Schüpfer F, Lehmann U, Sobota RM, Litchfield DW, Lüscher B, Chrast R, Suter U,

Senderek J.

Institute of Cell Biology, ETH Zürich, Schafmattstr 18, 8093 Zürich,

Switzerland.

Abstract

Patients with Charcot-Marie-Tooth neuropathy and gene targeting in mice revealed

an essential role for the SH3TC2 gene in peripheral nerve myelination. SH3TC2

expression is restricted to Schwann cells in the peripheral nervous system, and

the gene product, SH3TC2, localizes to the perinuclear recycling compartment.

Here, we show that SH3TC2 interacts with the small guanosine triphosphatase

Rab11, which is known to regulate the recycling of internalized membranes and

receptors back to the cell surface. Results of protein binding studies and

transferrin receptor trafficking are in line with a role of SH3TC2 as a Rab11

effector molecule. Consistent with a function of Rab11 in Schwann cell

myelination, SH3TC2 mutations that cause neuropathy disrupt the SH3TC2/Rab11

interaction, and forced expression of dominant negative Rab11 strongly impairs

myelin formation in vitro. Our data indicate that the SH3TC2/Rab11 interaction

is relevant for peripheral nerve pathophysiology and place endosomal recycling

on the list of cellular mechanisms involved in Schwann cell myelination.