title: Cerebral ischemic injury is enhanced in a model of oculodentodigital dysplasia.
abstract: Oculodentodigital dysplasia (ODDD) is a rare autosomal dominant disease that results in visible developmental anomalies of the limbs, face, eyes and teeth. Recently analysis of human connexin43 (Cx43) DNA sequences has revealed a number of different missense, duplication and frame shift mutations resulting in this phenotype. A mouse model of this disorder has been created with a missense point mutation of the glycine amino acid at position 60 to serine (G60S). Heterozygote +/G60S mice exhibit a similar ODDD phenotype as observed in humans. In addition to the malformations listed above, ODDD patients often have neurological findings. In the brain, Cx43 is highly expressed in astrocytes and has been shown to play a role in neuroprotection. We were interested in determining the effect of the +/G60S mutation following stroke. Four days after middle cerebral artery occlusion the volume of infarct was larger in mice with the +/G60S mutation. In astrocyte-neuron co-cultures, exposure to glutamate also resulted in greater cellular death in the +/G60S mutants. Protein levels of Cx43 in the mutant mouse were found to be reduced when compared to the normal tissue. Cx43 protein was observed as a continual line of small punctate aggregates in the plasma membrane with increased intracellular localization, which is distinct from the larger plaques seen in the normal mouse astrocytes. Functionally, primary +/G60S astrocytes exhibited reduced gap junctional coupling and increased hemichannel activity, which may underlie the mechanism of increased damage during stroke. This article is part of the Special Issue Section entitled 'Current Pharmacology of Gap Junction Channels and Hemichannels'.
authors.affiliation: Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kozoriz
authors.affiliation: Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Lai
authors.affiliation: Experimental Physiology Laboratory (EPhyL), Instituto Antofagasta, Antofagasta, Chile; Departamento de Fisiología, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: José L
authors.initials: JL
authors.lastname: Vega
authors.affiliation: Departamento de Fisiología, Pontificia Universidad Católica de Chile, Santiago, Chile; Instituto Milenio, Centro Interdiciplinario de Neurociencias de Valparaíso, Valparaíso, Chile.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Sáez
authors.affiliation: Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Wun Chey
authors.initials: WC
authors.lastname: Sin
authors.affiliation: Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: John F
authors.initials: JF
authors.lastname: Bechberger
authors.affiliation: Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada. Electronic address: cnaus@interchange.ubc.ca.
authors.forename: Christian C
authors.initials: CC
authors.lastname: Naus
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D020520:Brain Infarction / Q000209:etiology; D002545:Brain Ischemia / Q000503:physiopathology*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D018031:Connexin 43 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000150:complications* / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005124:Eye Abnormalities / Q000150:complications* / Q000235:genetics / Q000473:pathology; D005532:Foot Deformities, Congenital / Q000150:complications* / Q000235:genetics / Q000473:pathology; D017629:Gap Junctions / Q000473:pathology; D018698:Glutamic Acid / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects; D012694:Serine / Q000235:genetics; D013576:Syndactyly / Q000150:complications* / Q000235:genetics / Q000473:pathology; D014071:Tooth Abnormalities / Q000150:complications* / Q000235:genetics / Q000473:pathology
chemical_list: D018031:Connexin 43; D004791:Enzyme Inhibitors; C543076:GJA1 protein, mouse; D018698:Glutamic Acid; D012694:Serine
keywords: 4′,6-diamidino-2-phenylindole; Astrocytes; BSA; Connexin43; Cx43; DAPI; DMEM; Dulbecco's modified Eagle's medium; EBSS; Earle's balanced salt solution; Etd; G60S; GFAP; Gap junctional communication; HBSS; Hank's buffered salt solution; Hemichannels; IBA-1; LDH; La(3+); MCAO; ODDD; PI; RIPA; Rare genetic disease; Stroke; TBS-T; Tris-buffered saline with tween; bovine serum albumin; connexin43; ethidium; glial fibrillary acidic protein; ionized calcium-binding adaptor molecule 1; lactate dehydrogenase; lanthanum ion; middle cerebral artery occlusion; missense point mutation of the glycine amino acid at position 60 conversion to serine; oculodentodigital dysplasia; propidium iodide; radioimmune precipitation lysis buffer