Journal article
MpzR98C arrests Schwann cell development in a mouse model of early-onset Charcot–Marie–Tooth disease type 1B
Brain (London, England : 1878), Vol.135(7), pp.2032-2047
07/2012
DOI: 10.1093/brain/aws140
PMCID: PMC3381724
PMID: 22689911
Abstract
Mutations in myelin protein zero (
MPZ
) cause Charcot–Marie–Tooth disease type 1B. Many dominant
MPZ
mutations, including R98C, present as infantile onset dysmyelinating neuropathies. We have generated an R98C ‘knock-in’ mouse model of Charcot–Marie–Tooth type 1B, where a mutation encoding R98C was targeted to the mouse
Mpz
gene. Both heterozygous (R98C/+) and homozygous (R98C/R98C) mice develop weakness, abnormal nerve conduction velocities and morphologically abnormal myelin; R98C/R98C mice are more severely affected. MpzR98C is retained in the endoplasmic reticulum of Schwann cells and provokes a transitory, canonical unfolded protein response. Ablation of Chop, a mediator of the protein kinase RNA-like endoplasmic reticulum kinase unfolded protein response pathway restores compound muscle action potential amplitudes of R98C/+ mice but does not alter the reduced conduction velocities, reduced axonal diameters or clinical behaviour of these animals. R98C/R98C Schwann cells are developmentally arrested in the promyelinating stage, whereas development is delayed in R98C/+ mice. The proportion of cells expressing c-Jun, an inhibitor of myelination, is elevated in mutant nerves, whereas the proportion of cells expressing the promyelinating transcription factor Krox-20 is decreased, particularly in R98C/R98C mice. Our results provide a potential link between the accumulation of MpzR98C in the endoplasmic reticulum and a developmental delay in myelination. These mice provide a model by which we can begin to understand the early onset dysmyelination seen in patients with R98C and similar mutations.
Details
- Title: Subtitle
- MpzR98C arrests Schwann cell development in a mouse model of early-onset Charcot–Marie–Tooth disease type 1B
- Creators
- Mario A. C Saporta - 1 Department of Neurology, Wayne State University, Detroit, MI 48201, USABrian R Shy - 1 Department of Neurology, Wayne State University, Detroit, MI 48201, USAAgnes Patzko - 1 Department of Neurology, Wayne State University, Detroit, MI 48201, USAYunhong Bai - 1 Department of Neurology, Wayne State University, Detroit, MI 48201, USAMaria Pennuto - 3 Division of Genetics and Cell Biology, San Raffaele Scientific Institute, DIBIT, Milano 20132, ItalyCinzia Ferri - 3 Division of Genetics and Cell Biology, San Raffaele Scientific Institute, DIBIT, Milano 20132, ItalyElisa Tinelli - 3 Division of Genetics and Cell Biology, San Raffaele Scientific Institute, DIBIT, Milano 20132, ItalyPaola Saveri - 3 Division of Genetics and Cell Biology, San Raffaele Scientific Institute, DIBIT, Milano 20132, ItalyDan Kirschner - 5 Biology Department, Boston College, Chestnut Hill, MA 02467-3804, USAMichelle Crowther - 5 Biology Department, Boston College, Chestnut Hill, MA 02467-3804, USACherie Southwood - 6 Centre for Molecular Medicine and Genetics, Wayne State University 48201, Detroit, MI, USAXingyao Wu - 1 Department of Neurology, Wayne State University, Detroit, MI 48201, USAAlexander Gow - 1 Department of Neurology, Wayne State University, Detroit, MI 48201, USAM. Laura Feltri - 3 Division of Genetics and Cell Biology, San Raffaele Scientific Institute, DIBIT, Milano 20132, ItalyLawrence Wrabetz - 3 Division of Genetics and Cell Biology, San Raffaele Scientific Institute, DIBIT, Milano 20132, ItalyMichael E Shy - 1 Department of Neurology, Wayne State University, Detroit, MI 48201, USA
- Resource Type
- Journal article
- Publication Details
- Brain (London, England : 1878), Vol.135(7), pp.2032-2047
- Publisher
- Oxford University Press
- DOI
- 10.1093/brain/aws140
- PMID
- 22689911
- PMCID
- PMC3381724
- ISSN
- 0006-8950
- eISSN
- 1460-2156
- Language
- English
- Date published
- 07/2012
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984020641502771
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