Accelerated demyelination of peripheral nerves in mice deficient in connexin 32 and protein zero.
Mutant mice that lack either protein zero (P0) or connexin 32 (Cx32) were generated previously to investigate the function of these myelin proteins in peripheral nerves and to assess the value of these mice as animal models for hereditary human peripheral neuropathies. Mice that are completely devoid of P0 expression (P0(+/0)) show a complex phenotype that is characterized by hypomyelination, compromised myelin compaction, and degeneration of myelin and axons early in life. In contrast, young mouse mutants that have retained one wild-type allele of the P0 gene (P0(+/0)) reveal morphologically normal myelin but start to develop signs of demyelination and remyelination at 4 months of age. A similar late-onset myelin deficiency was observed in Cx32-deficient mice (Cx32(0/0)). We have now generated mice deficient for Cx32 and P0. In animals that lack both proteins (Cx32(0/0)/P0(0/0), the phenotype is morphologically identical to mice that solely lack P0. Animals that lack Cx32 and carry one functional P0 allele (Cx32(0/0/P0(+/0)) revealed demyelination and remyelination as evidenced by thin myelin and Schwann cell onion bulb formation already at the age of 4 weeks, a time point when no pathology was observed in the single mutants. These morphological deficits were also more prominent in 4-month-old Cx32(0/0)/P0(+/0)animals compared to the single mutants. Our data support the view that Cx32 and P0 are crucial molecules for the maintenance of myelin. Furthermore, the function of Cx32 in the peripheral nervous system appears to be largely dispensable when myelin compaction is impaired.
Neuberg
D H
DH
Department of Cell Biology, Swiss Federal Institute of Technology, Zürich.
Carenini
S
S
Schachner
M
M
Martini
R
R
Suter
U
U
D000483:Alleles; D000818:Animals; D001369:Axons / Q000648:ultrastructure; D017630:Connexins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003711:Demyelinating Diseases / Q000473:pathology*; D006579:Heterozygote; D006720:Homozygote; D051379:Mice; D009154:Mutation; D018993:Myelin P0 Protein / Q000235:genetics / Q000502:physiology*; D009186:Myelin Sheath / Q000648:ultrastructure*; D010243:Paralysis; D010525:Peripheral Nerves / Q000648:ultrastructure*; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012583:Schwann Cells / Q000648:ultrastructure; D016138:Walking; D000097002:Gap Junction beta-1 Protein
D017630:Connexins; D018993:Myelin P0 Protein; D000097002:Gap Junction beta-1 Protein