Kir4.1 potassium channel subunit is crucial for oligodendrocyte development and in vivo myelination.
To understand the cellular and in vivo functions of specific K(+) channels in glia, we have studied mice with a null mutation in the weakly inwardly rectifying K(+) channel subunit Kir4.1. Kir4.1-/- mice display marked motor impairment, and the cellular basis is hypomyelination in the spinal cord, accompanied by severe spongiform vacuolation, axonal swellings, and degeneration. Immunostaining in the spinal cord of wild-type mice up to postnatal day 18 reveals that Kir4.1 is expressed in myelin-synthesizing oligodendrocytes, but probably not in neurons or glial fibrillary acidic protein-positive (GFAP-positive) astrocytes. Cultured oligodendrocytes from developing spinal cord of Kir4.1-/- mice lack most of the wild-type K(+) conductance, have depolarized membrane potentials, and display immature morphology. By contrast, cultured neurons from spinal cord of Kir4.1-/- mice have normal physiological characteristics. We conclude that Kir4.1 forms the major K(+) conductance of oligodendrocytes and is therefore crucial for myelination. The Kir4.1 knock-out mouse is one of the few CNS dysmyelinating or demyelinating phenotypes that does not involve a gene directly involved in the structure, synthesis, degradation, or immune response to myelin. Therefore, this mouse shows how an ion channel mutation could contribute to the polygenic demyelinating diseases.
Neusch
C
C
Division of Biology, California Institute of Technology, Pasadena, California 91125, USA.
Rozengurt
N
N
Jacobs
R E
RE
Lester
H A
HA
Kofuji
P
P
D000818:Animals; D017209:Apoptosis; D001369:Axons / Q000473:pathology / Q000648:ultrastructure; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D018390:Gene Targeting; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010641:Phenotype; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D021122:Protein Subunits; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013118:Spinal Cord Diseases / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D015996:Survival Rate; D014202:Tremor / Q000209:etiology; D014617:Vacuoles / Q000473:pathology / Q000648:ultrastructure
D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D021122:Protein Subunits; D011188:Potassium