Preserved myelin integrity and reduced axonopathy in connexin32-deficient mice lacking the recombination activating gene-1.
Mice heterozygously deficient for myelin protein zero (P0) mimicking human Charcot-Marie-Tooth (CMT) disease 1B show T-lymphocyte and macrophage upregulation in peripheral nerves, which aggravates and modulates the genetically mediated demyelinating neuropathy. In connexin32 (cx32)-deficient (cx32(def)) mice, which mimic the X-linked dominant form of CMT (CMTX), T-lymphocyte and macrophage numbers are also significantly elevated in peripheral nerves. To test the hypothesis that immune cells are indeed pathogenic in this model, we cross-bred cx32(def) mice with recombination activating gene-1 (RAG-1)-deficient mice, which lack mature T- and B-lymphocytes. In these immunoincompetent double mutants, the number of endoneurial macrophages was reduced. Furthermore, features indicative of myelin degeneration and axonopathic changes were mitigated in the RAG-1-deficient double mutants, whereas enlarged periaxonal Schwann cell collars, a hallmark specific for cx32-mutants, were not reduced. Since both cx32- and P0 deficiency lead to similar immunopathogenic processes, we conclude that immune-mediated demyelination may be a feature common to many CMT-like neuropathies independent of the genetic origin.
Kobsar
I
I
Department of Neurology, University of Würzburg, Würzburg, Germany.
Berghoff
M
M
Samsam
M
M
Wessig
C
C
Mäurer
M
M
Toyka
K V
KV
Martini
R
R
D000818:Animals; D001369:Axons / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D017630:Connexins / Q000172:deficiency* / Q000235:genetics; D003711:Demyelinating Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016654:Genes, RAG-1 / Q000235:genetics*; D005838:Genotype; D006579:Heterozygote; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D018482:Muscle, Skeletal / Q000294:innervation; D009186:Myelin Sheath / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D015854:Up-Regulation
D017630:Connexins; C099106:Gja6 protein, rat