MpzR98C arrests Schwann cell development in a mouse model of early-onset Charcot-Marie-Tooth disease type 1B.
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.
Department of Neurology, Wayne State University, Detroit, MI 48201, USA.
Mario A C
MA
Saporta
Brian R
BR
Shy
Agnes
A
Patzko
Yunhong
Y
Bai
Maria
M
Pennuto
Cinzia
C
Ferri
Elisa
E
Tinelli
Paola
P
Saveri
Dan
D
Kirschner
Michelle
M
Crowther
Cherie
C
Southwood
Xingyao
X
Wu
Alexander
A
Gow
M Laura
ML
Feltri
Lawrence
L
Wrabetz
Michael E
ME
Shy
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001369:Axons / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D002454:Cell Differentiation / Q000502:physiology*; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D051767:Early Growth Response Protein 2 / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D055879:Gene Knock-In Techniques / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D018993:Myelin P0 Protein / Q000235:genetics / Q000502:physiology*; D009186:Myelin Sheath / Q000235:genetics / Q000473:pathology; D009431:Neural Conduction / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D045442:Rotarod Performance Test / Q000379:methods; D012583:Schwann Cells / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D051742:Transcription Factor CHOP / Q000378:metabolism; D056811:Unfolded Protein Response / Q000502:physiology
C497250:Ddit3 protein, mouse; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D018993:Myelin P0 Protein; D016755:Proto-Oncogene Proteins c-jun; D051742:Transcription Factor CHOP