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Cerebral ischemic injury is enhanced in a model of oculodentodigital dysplasia.
Neuropharmacology. 2013 Dec; 75:549-56.N

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+Show Affiliations

Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.Experimental Physiology Laboratory (EPhyL), Instituto Antofagasta, Antofagasta, Chile; Departamento de Fisiología, Pontificia Universidad Católica de Chile, Santiago, Chile.Departamento de Fisiología, Pontificia Universidad Católica de Chile, Santiago, Chile; Instituto Milenio, Centro Interdiciplinario de Neurociencias de Valparaíso, Valparaíso, Chile.Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada. Electronic address: cnaus@interchange.ubc.ca.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23727526

Citation

Kozoriz, Michael G., et al. "Cerebral Ischemic Injury Is Enhanced in a Model of Oculodentodigital Dysplasia." Neuropharmacology, vol. 75, 2013, pp. 549-56.
Kozoriz MG, Lai S, Vega JL, et al. Cerebral ischemic injury is enhanced in a model of oculodentodigital dysplasia. Neuropharmacology. 2013;75:549-56.
Kozoriz, M. G., Lai, S., Vega, J. L., Sáez, J. C., Sin, W. C., Bechberger, J. F., & Naus, C. C. (2013). Cerebral ischemic injury is enhanced in a model of oculodentodigital dysplasia. Neuropharmacology, 75, 549-56. https://doi.org/10.1016/j.neuropharm.2013.05.003
Kozoriz MG, et al. Cerebral Ischemic Injury Is Enhanced in a Model of Oculodentodigital Dysplasia. Neuropharmacology. 2013;75:549-56. PubMed PMID: 23727526.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cerebral ischemic injury is enhanced in a model of oculodentodigital dysplasia. AU - Kozoriz,Michael G, AU - Lai,Simon, AU - Vega,José L, AU - Sáez,Juan C, AU - Sin,Wun Chey, AU - Bechberger,John F, AU - Naus,Christian C, Y1 - 2013/05/31/ PY - 2013/01/02/received PY - 2013/05/01/revised PY - 2013/05/04/accepted PY - 2013/6/4/entrez PY - 2013/6/4/pubmed PY - 2014/8/20/medline KW - 4′,6-diamidino-2-phenylindole KW - Astrocytes KW - BSA KW - Connexin43 KW - Cx43 KW - DAPI KW - DMEM KW - Dulbecco's modified Eagle's medium KW - EBSS KW - Earle's balanced salt solution KW - Etd KW - G60S KW - GFAP KW - Gap junctional communication KW - HBSS KW - Hank's buffered salt solution KW - Hemichannels KW - IBA-1 KW - LDH KW - La(3+) KW - MCAO KW - ODDD KW - PI KW - RIPA KW - Rare genetic disease KW - Stroke KW - TBS-T KW - Tris-buffered saline with tween KW - bovine serum albumin KW - connexin43 KW - ethidium KW - glial fibrillary acidic protein KW - ionized calcium-binding adaptor molecule 1 KW - lactate dehydrogenase KW - lanthanum ion KW - middle cerebral artery occlusion KW - missense point mutation of the glycine amino acid at position 60 conversion to serine KW - oculodentodigital dysplasia KW - propidium iodide KW - radioimmune precipitation lysis buffer SP - 549 EP - 56 JF - Neuropharmacology JO - Neuropharmacology VL - 75 N2 - 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'. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/23727526/Cerebral_ischemic_injury_is_enhanced_in_a_model_of_oculodentodigital_dysplasia_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(13)00212-8 DB - PRIME DP - Unbound Medicine ER -