Induced myelination and demyelination in a conditional mouse model of Charcot-Marie-Tooth disease type 1A

被引:75
作者
Perea, J
Robertson, A
Tolmachova, T
Muddle, J
King, RHM
Ponsford, S
Thomas, PK
Huxley, C
机构
[1] Imperial Coll, Sch Med, Div Biomed Sci, London SW7 2AZ, England
[2] UCL Royal Free & Univ Coll, Sch Med, Dept Clin Neurosci, London NW3 2PF, England
[3] Inst Neurol, London WC1N 3BG, England
[4] St Bartholomews Hosp, Dept Clin Neurophysiol, London, England
关键词
D O I
10.1093/hmg/10.10.1007
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Charcot-Marie-Tooth disease type 1A, a hereditary demyelinating neuropathy, is usually caused by overexpression of peripheral myelin protein 22 (PMP22) due to a genomic duplication, We have generated a transgenic mouse model in which mouse pmp22 overexpression can be regulated. In this mouse model, overexpression of pmp22 occurs specifically in Schwann cells of the peripheral nerve and is switched off when the mice are fed tetracycline. Overexpression of pmp22 throughout life (in the absence of tetracycline) causes demyelination. In contrast, myelination is nearly normal when pmp22 overexpression is switched off throughout life by feeding the mice tetracycline, When overexpression of pmp22 is switched off in adult mice, correction begins within 1 week and myelination is well advanced by 3 months (although the myelin sheaths are still thinner than normal), indicating that the Schwann cells are poised to start myelination, Upregulation of the gene in adult mice (which had previously had normal pmp22 expression) is followed by active demyelination within 1 week, which had plateaued by 8 weeks, This indicates that Schwann cells with mature myelin are sensitive to increased amounts of pmp22 such that they rapidly demyelinate. Thus, demyelination can largely be corrected within a few months, but the correction will be sensitive to subsequent upregulation of pmp22.
引用
收藏
页码:1007 / 1018
页数:12
相关论文
共 39 条
[1]   HYPERMYELINATION AND DEMYELINATING PERIPHERAL NEUROPATHY IN PMP22-DEFICIENT MICE [J].
ADLKOFER, K ;
MARTINI, R ;
AGUZZI, A ;
ZIELASEK, J ;
TOYKA, KV ;
SUTER, U .
NATURE GENETICS, 1995, 11 (03) :274-280
[2]   ABNORMAL MYELINATION IN TRANSPLANTED TREMBLER MOUSE SCHWANN-CELLS [J].
AGUAYO, AJ ;
ATTIWELL, M ;
TRECARTEN, J ;
PERKINS, S ;
BRAY, GM .
NATURE, 1977, 265 (5589) :73-75
[3]  
BALLIN RHM, 1969, J NEUROL SCI, V8, P225
[4]   Exposure at the cell surface is required for Gas3/PMP22 to regulate both cell death and cell spreading: Implication for the Charcot-Marie-Tooth type 1A and Dejerine-Sottas diseases [J].
Brancolini, C ;
Edomi, P ;
Marzinotto, S ;
Schneider, C .
MOLECULAR BIOLOGY OF THE CELL, 2000, 11 (09) :2901-2914
[5]   TRANSFORMATION OF YEAST SPHEROPLASTS WITHOUT CELL-FUSION [J].
BURGERS, PMJ ;
PERCIVAL, KJ .
ANALYTICAL BIOCHEMISTRY, 1987, 163 (02) :391-397
[6]   DNA DELETION ASSOCIATED WITH HEREDITARY NEUROPATHY WITH LIABILITY TO PRESSURE PALSIES [J].
CHANCE, PF ;
ALDERSON, MK ;
LEPPIG, KA ;
LENSCH, MW ;
MATSUNAMI, N ;
SMITH, B ;
SWANSON, PD ;
ODELBERG, SJ ;
DISTECHE, CM ;
BIRD, TD .
CELL, 1993, 72 (01) :143-151
[7]  
D'Urso D, 1999, J NEUROSCI, V19, P3396
[8]  
D'Urso D, 1998, J NEUROSCI, V18, P731
[10]   SR13/PMP-22 EXPRESSION IN RAT NERVOUS-SYSTEM, IN PC12 CELLS, AND C6 GLIAL-CELL LINES [J].
DELEON, M ;
NAHIN, RL ;
MENDOZA, ME ;
RUDA, MA .
JOURNAL OF NEUROSCIENCE RESEARCH, 1994, 38 (02) :167-181