Panglial gap junctional communication is essential for maintenance of myelin in the CNS.
In this study, we have investigated the contribution of oligodendrocytic connexin47 (Cx47) and astrocytic Cx30 to panglial gap junctional networks as well as myelin maintenance and function by deletion of both connexin coding DNAs in mice. Biocytin injections revealed complete disruption of oligodendrocyte-to-astrocyte coupling in the white matter of 10- to 15-d-old Cx30/Cx47 double-deficient mice, while oligodendrocyte-to-oligodendrocyte coupling was maintained. There were no quantitative differences regarding cellular networks in acute brain slices obtained from Cx30/Cx47 double-null mice and control littermates, probably caused by the upregulation of oligodendrocytic Cx32 in Cx30/Cx47 double-deficient mice. We observed early onset myelin pathology, and ∼40% of Cx30/Cx47 double-deficient animals died within 42 to 90 d after birth, accompanied by severe motor impairments. Histological and ultrastructural analyses revealed severe vacuolization and myelination defects in all white matter tracts of the CNS. Furthermore, Cx30/Cx47 double-deficient mice exhibited a decreased number of oligodendrocytes, severe astrogliosis, and microglial activation in white matter tracts. Although less affected concerning motor impairment, surviving double-knock-out (KO) mice showed behavioral alterations in the open field and in the rotarod task. Vacuole formation and thinner myelin sheaths were evident also with adult surviving double-KO mice. Since interastrocytic coupling due to Cx43 expression and interoligodendrocytic coupling because of Cx32 expression are still maintained, Cx30/Cx47 double-deficient mice demonstrate the functional role of both connexins for interastrocytic, interoligodendrocytic, and panglial coupling, and show that both connexins are required for maintenance of myelin.
Institute of Genetics, Division of Molecular Genetics, University of Bonn, 53117 Bonn, Germany.
Oliver
O
Tress
Marta
M
Maglione
Dennis
D
May
Tatjyana
T
Pivneva
Nadine
N
Richter
Julia
J
Seyfarth
Sonja
S
Binder
Armin
A
Zlomuzica
Gerald
G
Seifert
Martin
M
Theis
Ekrem
E
Dere
Helmut
H
Kettenmann
Klaus
K
Willecke
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001703:Biophysics; D002490:Central Nervous System / Q000166:cytology* / Q000254:growth & development; D000075302:Connexin 30; D017630:Connexins / Q000172:deficiency / Q000378:metabolism; D004558:Electric Stimulation; D005106:Exploratory Behavior / Q000502:physiology; D017629:Gap Junctions / Q000502:physiology* / Q000648:ultrastructure; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006185:Habituation, Psychophysiologic / Q000235:genetics; D066298:In Vitro Techniques; D053208:Kaplan-Meier Estimate; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009043:Motor Activity / Q000235:genetics; D009186:Myelin Sheath / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology* / Q000502:physiology / Q000648:ultrastructure; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000166:cytology* / Q000502:physiology / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D011597:Psychomotor Performance / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D021641:Recognition, Psychology / Q000502:physiology; D016622:Silver Staining; D018709:Statistics, Nonparametric; D000097002:Gap Junction beta-1 Protein
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D000199:Actins; D051792:Basic Helix-Loop-Helix Proteins; D000075302:Connexin 30; D017630:Connexins; D005904:Glial Fibrillary Acidic Protein; D049452:Green Fluorescent Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D012333:RNA, Messenger; D000097002:Gap Junction beta-1 Protein; C100629:Gjb6 protein, mouse; C512773:Olig2 protein, mouse; C427305:connexin 47; C485184:enhanced green fluorescent protein