SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system
- Estelle Arnauda,
- Jennifer Zenkera,b,
- Anne-Sophie de Preux Charlesa,
- Claudia Stendelc,
- Andreas Roosd,
- Jean-Jacques Médarda,
- Nicolas Tricaudc,
- Joachim Weise,
- Ueli Suterc,
- Jan Senderekc,d,e and
- Roman Chrasta,1
- aDepartment of Medical Genetics and
- bGraduate Program in Neurosciences, University of Lausanne, CH-1005 Lausanne, Switzerland;
- cInstitute of Cell Biology, Eidgenössische Technische Hochschule (ETH) Zurich, CH-8093 Zurich, Switzerland; and
- Institute of dHuman Genetics, Rheinisch-Westfälische Technische Hochschule (RWTH), Aachen University of Technology, 52074 Aachen, Germany and
- Institute of eNeuropathology, Rheinisch-Westfälische Technische Hochschule (RWTH), Aachen University of Technology, 52074 Aachen, Germany
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Edited by Eric M. Shooter, Stanford University School of Medicine, Stanford, CA, and approved July 29, 2009 (received for review May 26, 2009)
Abstract
Charcot–Marie–Tooth disease type 4C (CMT4C) is an early-onset, autosomal recessive form of demyelinating neuropathy. The clinical manifestations include progressive scoliosis, delayed age of walking, muscular atrophy, distal weakness, and reduced nerve conduction velocity. The gene mutated in CMT4C disease, SH3TC2/KIAA1985, was recently identified; however, the function of the protein it encodes remains unknown. We have generated knockout mice where the first exon of the Sh3tc2 gene is replaced with an enhanced GFP cassette. The Sh3tc2ΔEx1/ΔEx1 knockout animals develop progressive peripheral neuropathy manifested by decreased motor and sensory nerve conduction velocity and hypomyelination. We show that Sh3tc2 is specifically expressed in Schwann cells and localizes to the plasma membrane and to the perinuclear endocytic recycling compartment, concordant with its possible function in myelination and/or in regions of axoglial interactions. Concomitantly, transcriptional profiling performed on the endoneurial compartment of peripheral nerves isolated from control and Sh3tc2ΔEx1/ΔEx1 animals uncovered changes in transcripts encoding genes involved in myelination and cell adhesion. Finally, detailed analyses of the structures composed of compact and noncompact myelin in the peripheral nerve of Sh3tc2ΔEx1/ΔEx1 animals revealed abnormal organization of the node of Ranvier, a phenotype that we confirmed in CMT4C patient nerve biopsies. The generated Sh3tc2 knockout mice thus present a reliable model of CMT4C neuropathy that was instrumental in establishing a role for Sh3tc2 in myelination and in the integrity of the node of Ranvier, a morphological phenotype that can be used as an additional CMT4C diagnostic marker.
Footnotes
- 1To whom correspondence should be addressed. E-mail: roman.chrast{at}unil.ch
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Author contributions: E.A., J.S., and R.C. designed research; E.A., J.Z., A.-S.d.P.C., C.S., A.R., J.-J.M., N.T., and R.C. performed research; E.A., J.Z., A.-S.d.P.C., C.S., A.R., J.W., U.S., J.S., and R.C. analyzed data; and E.A., N.T., J.W., U.S., J.S., and R.C. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS Direct Submission.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0905523106/DCSupplemental.
