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.
| Original language | English |
|---|---|
| Pages (from-to) | 2032-2047 |
| Number of pages | 16 |
| Journal | Brain |
| Volume | 135 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - 2012 |
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Keywords
- Charcot-Marie-Tooth type 1B
- Demyelination
- Glial cells
- Neuromuscular disorders
- Neuropathy
ASJC Scopus subject areas
- Clinical Neurology
Cite this
MpzR98C arrests Schwann cell development in a mouse model of early-onset Charcot-Marie-Tooth disease type 1B. / Saporta, Mario A C; Shy, Brian R.; Patzko, Agnes; Bai, Yunhong; Pennuto, Maria; Ferri, Cinzia; Tinelli, Elisa; Saveri, Paola; Kirschner, Dan; Crowther, Michelle; Southwood, Cherie; Wu, Xingyao; Gow, Alexander; Feltri, M. Laura; Wrabetz, Lawrence; Shy, Michael E.
In: Brain, Vol. 135, No. 7, 2012, p. 2032-2047.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - MpzR98C arrests Schwann cell development in a mouse model of early-onset Charcot-Marie-Tooth disease type 1B
AU - Saporta, Mario A C
AU - Shy, Brian R.
AU - Patzko, Agnes
AU - Bai, Yunhong
AU - Pennuto, Maria
AU - Ferri, Cinzia
AU - Tinelli, Elisa
AU - Saveri, Paola
AU - Kirschner, Dan
AU - Crowther, Michelle
AU - Southwood, Cherie
AU - Wu, Xingyao
AU - Gow, Alexander
AU - Feltri, M. Laura
AU - Wrabetz, Lawrence
AU - Shy, Michael E.
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Charcot-Marie-Tooth type 1B
KW - Demyelination
KW - Glial cells
KW - Neuromuscular disorders
KW - Neuropathy
UR - http://www.scopus.com/inward/record.url?scp=84863203827&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84863203827&partnerID=8YFLogxK
U2 - 10.1093/brain/aws140
DO - 10.1093/brain/aws140
M3 - Article
C2 - 22689911
AN - SCOPUS:84863203827
VL - 135
SP - 2032
EP - 2047
JO - Brain
JF - Brain
SN - 0006-8950
IS - 7
ER -