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Gap Junctions in Neural Development and Disease
Gap junctions are collections of intercellular membrane channels that join adjacent cells in every organ of the body. They allow a variety of small molecules to pass freely from cell to cell, coupling the cells metabolically and allowing them to coordinate their responses to various signals. The importance of gap junctions has become evident with the identification of congenital diseases resulting from mutations in connexin genes, including X-linked Charcot-Marie-Tooth disease, congenital cataracts, deafness, heart defects and skin diseases. In addition, reduced gap junctional coupling between cells has been detected in several cancers, and increased coupling has implications for epilepsy and stroke. Most of these disease syndromes, to greater or lesser extent, are reproduced in transgenic mice lacking specific connexins.
The objective of my research program is to explore the role of gap junctions in neural development and disease, including consequences of connexin mutations on gap junction structure and function, and to explore the role of these intercellular channels in diagnosis of disease and development of novel therapeutic strategies.
My research in developmental neuroscience is aimed at exploring the function of gap junctional coupling in the developing brain, using pharmacological manipulation as well as genetically modified mice designed to express normal and mutant connexin genes with specific temporal and spatial expression patterns. The role of gap junctions in the etiology and possible therapy of neurological disorders is being examined in animal models and clinical tissues related to stroke, epilepsy and brain cancer. In the area of cell biology and cancer research, we have shown that tumour cells engineered to re-establish gap junctional communication show suppression in growth and tumorigenesis. A major focus of ongoing research is aimed at determining the mechanisms underlying this tumour-suppressive effect, using genomics approaches to identify some of the links between gap junctions and expression of growth control genes. We are also exploring the repertoire of endogenous molecules which pass through gap junction channels, some of which are likely to be involved in the control of cell growth and differentiation. Given the evidence that some tumour therapeutic agents readily pass through gap junctions to enhance tumour cell killing, this research is particularly relevant to the development of novel cancer therapies. |
Foger, N., M.A. Retamal, E. Amigou, M.G. Kozoriz, C.C. Naus, J.C. Saez and C. Giaume (2010). The activation of Cx43 hemichannels is astrocytes triggered by proinflammatory cytokines enhances NMDA-induced neurotoxicity. Mol. Cell. Neurosci. 45:37-46.
Herrero-Gonzalez, S., C. Giaume, C.C. Naus, J.M. Medina and A. Tabernero. (2010). Connexin43 inhibits the oncogenic activity of c-Src in glioma cells. Oncogene, Epub Aug. 2.
Kozoriz, M.G., J. Church, M.A. Ozog, C.C. Naus and C. Krebs. (2010). Temporary sequestration of potassium by mitochondria in astrocytes. J. Biol. Chem., Epub July 28.
Naus, C.C. and D.W. Laird. (2010). Implications and challenges of connexin connections in cancer. Nature Reviews Cancer 10:435-441.
Kozoriz, M.G., J.F. Bechberger, G. Bechberger, K. Mass, K. Willecke and C.C. Naus. (2010). Removal of the C-terminus of connexin43 results in enhanced damage during stroke. J. Neuropath. Exp. Neurol. 69:196-206. Epub 2010 Jan. 13.
Guttman, J.A., A.E. Lin, Y. Li, J. Bechberger, C.C. Naus, A.W. Vogl and B.B. Finlay (2010). Gap junction hemichannels contribute to the generation of diarrhea during infectious enteric disease. Gut 59:218-226. Epub 2009 Oct. 14.
Crespin, S., J.F. Bechberger, M. Mesnil, C.C. Naus and W.C. Sin. (2010). The carboxy-terminal tail of Connexin43 gap junction protein is sufficient to mediate cytoskeletal changes in human glioma cells. J. Cell. Biochem. in press.
Decrock, E., E. De Vuyst, M. Van Moorhem, L. Laeken, M. De Bock, M. Vinken, V. Rogiers, K. D’Herde, W.H. Evans, C.C. Naus and L. Leybaert. (2009). Connexin43 hemichannels contribute to the propagation of apoptotic cell death in a rat C6 glioma cell model. Cell Death & Differentiation 16:151-163. Epub 2008 Sep 26.
Cina, C., M. Theis, K. Willecke, K. Maass, J.F. Bechberger and C.C. Naus. (2009). Involvement of the C-terminal of Connexin43 in neuronal migration. J. Neurosci. 29:2009-2021.
Van Slyke, J.K., C.C. Naus and L.S. Musil. (2009) Conformational maturation and post-ERmultisubunit assembly of gap junction proteins. Mol. Biol. Cell 20:2451-2463.
De Vuyst, E., E. Doecrock, M. De Bock, M. Van Moorhem, C. Lai, H. Yamasaki, C.C. Naus. W.H. Evans and L. Leybaert. (2009). Calcium-activation and inactivation of ATP release via connexin43 hemichannels is controlled by a calmodulin-arachidonic acid-ROS/NO signaling cascade. Cell Calcium 46:176-87. Epub 2009 Aug 4.
Lai, C.P.K., J. Bechberger and C.C. Naus. (2009). Panx2 as a novel growth suppressor in C6 glioma cells. Oncogene 28:4402-4408. Epub 2009 Sept 14.
Sin, W.C., M. Tse, N. Planque, B. Perbal, P.D. Lampe and C.C. Naus. (2009). Matricellular protein CCN3 regulates actin cytoskeleton reoganziation. J. Biol. Chem., 284:29935-44. Epub 2009 Aug 25.
Sin, W.C., D.C. Bates, J.F. Bechberger, W. Rushlow and C.C. Naus. (2008). Dose-dependent differential upregulation of CCN1/Cyr61 and CCN3/NOV by the gap junction protein connexin43 in glioma cells. J. Cell. Biochem. 103:1772-1782.
De Vuyst, E., M. De Bock, E. Doecrock, M. Van Moorhem, C.C. Naus, B. Blanchaert, C. Mabilde and L. Leybaert. (2008). In situ bipolar electroporation for localized cell loading with reporter dyes and investigating gap junctional coupling; Biophy. J. Biophys J. 94:469-479.
Ozog, M.A., G. Modha, J. Church, R. Reilley and C.C. Naus. (2008). Co-administration of CNTF with its soluble receptor protects against neuronal death and enhances neurite outgrowth. J. Biol. Chem. 283:6546-6560.
De Vuyst, E., E. Doecrock, M. De Bock, H. Yamasaki, C.C. Naus, W.H. Evans and L. Leybaert. (2007). Connexin hemichannels and gap junction channels are differentially influenced by lipopolysaccharide and bFGF. Mol Biol Cell. 18:34-46.
Conklin, C., J. Bechberger, D. MacFabe, N. Guthrie, E. Kurowska and C.C. Naus. (2007). Genistein and quercetin increase connexin43 and suppress growth of breast cancer cells. Carcinogenesis 28:93-107.
Lai, C.P.K., J.F. Bechberger, R. Thompson, B. MacVicar, R. Bruzzone and C.C. Naus. (2007). Tumour suppressive effects of Panx1 in C6 glioma cells. Cancer Research 67:1545-1554.
Cina, C., J.F. Bechberger, M.A. Ozog and C.C. Naus. (2007). Expression of connexins in embryonic mouse neocortical development. J. Comp. Neurol. 504:298-313.
Conklin C., D, Huntsman, N. Makretsov, D. Turbin and C.C. Naus. (2007). Tissue Microarray Analysis of Cx26, Cx32, Cx43 expression and its prognostic significance in human breast cancer. Cancer Letters 255:284-298.
Bates, D., W.C. Sin, Q. Aftab and C.C. Naus. (2007). Connexin43 enhances glioma invasion by a mechanism involving the carboxy terminus. Glia 55:1554-64.
Hamaguchi T., Y. Matsuoka, J. Bechberger, T. Ohnishi, K.I. Fujita, C.C. Naus, M. Kusunoki, A. Tsubura, H. Tsuda. (2006). Establishment of an apoptosis-sensitive rat mammary carcinoma cell line with a mutation in the DNA-binding region of p53. Cancer Lett. 232:279-288.
De Vuyst, E., E. Doecrock, L. Cabooter, G. Dubyak, C.C. Naus, W.H. Evans and L. Leybaert. (2006). Intracellular calcium changes trigger connexin32 hemichannel opening. EMBO Journal 25:34-44.
Jimenez, T., W.P. Fox, C.C. Naus, J. Galipeau, and Belliveau, D.J. (2006). Connexin Overexpression Differentially Suppresses Glioma Growth and Contributes to the Bystander Effect Following HSV-Thymidine Kinase Gene Therapy. Cell Adhes. Commun. 13:79-92.
Belliveau, D.J., M. Bani-Yaghoub, R. McGirr, C.C. Naus and W.R. Rushlow. (2006). Enhanced neurite outgrowth in PC12 cells mediated by connexin hemi-channels and ATP. J. Biol. Chem. 281:20920-20931.
Valiunas, V., J.F. Bechberger, C.C. Naus, P.R. Brink and G.S. Goldberg. (2005). Nontransformed cells normalize gap junctional communication with transformed cells. Biochem. Biophy. Res. Comm. 333:174-179.
Wentlandt K., P.L. Carlen, M. Kushnir, C.C. Naus and H. El-Beheiry. (2005). General anesthetics attenuate gap junction coupling in P19 cell line. J. Neurosci. Res. 81:746-752.
Zhang, Z., Y. Hu, B. Wnag, Z. Lin, C.C. Naus and B.J. Nicholson. (2004). The asymmetric gap junctional intercellular communication between human normal lung fibroblasts and malignant lung carcinoma cells. Carcinogenesis 25:473-482.
Nakase, T. and C.C. Naus. (2004). Gap junctions and neurological disorders of the central nervous system, in Biomembranes Special Issue: The Connexins, Biochem. Biophys. Acta 1662:149-158.
Alexander, D.B., H. Ichikawa, J.F. Bechberger, V. Valiunas, M. Ohki, C.C. Naus, T. Kunimoto, H. Tsuda, W.T. Miller and G.S. Goldberg. (2004). Normal cells control the growth of neighboring transformed cells independent of gap junctional communication and Src activity. Cancer Research 64:1347-1358.
Nakase, T., G. Sohl, M. Theiss, K. Willecke and C.C. Naus. (2004). Increased apoptosis and inflammation following focal brain ischemia in mice lacking connexin43 in astrocytes. American J. Pathology 164:2067-2075.
Fu, C., J.F. Bechberger, M. Ozog, B. Perbal and C.C. Naus. (2004). CCN3 (NOV) interacts with connexin43 in glioma cells: Possible mechanism of connexin-mediated growth suppression. J. Biol. Chem. 279:36943-36950.
Wentlandt K., M. Kushnir, C.C. Naus, and P.L. Carlen. (2004). Ethanol inhibits gap junctional coupling between P19 cells. Alcoholism: Clin. Exp. Res. 28:1284-1290.
Ozog, M.A., S.M. Bernier, D.C. Bates, B. Chaterjee, C.W. Lo and C.C. Naus. (2004). CNTF-CNTFRa complex upregulates connexin43 and intercellular coupling in astrocytes via the JAK/STAT pathway. Mol. Biol. Cell 15:4761-4774.
Frantseva, M.V., C.C. Naus and J.L. Perez Velazquez. (2003). Gap junctions and neuronal injury: protectants or executioners? The Neuroscientist 9:5-9.
Fushiki, S., J.L. Perez Velazquez, L. Zhang, C. Kinoshita, J.F. Bechberger, P.L. Carlen and C.C. Naus. (2003). Disruption of neuronal migration in neocortex of connexin43-null mutant mice. J. Neuropath. Exp. Neurol., 63:304-314.
Brigstock D.R., R. Goldschmeding, K.I. Katsube, S.C. Lam, L.F. Lau, K. Lyons, C.C. Naus, B. Perbal, B. Riser, M. Takigawa, and H. Yeger. (2003). Proposal for a unified CCN nomenclature. Mol Pathol 56:127-128.
Nakase, T., S. Fushiki and C.C. Naus. (2003). Astrocytic gap junctions composed of connexin43 reduce apoptotic neuronal damage in cerebral ischemia. Stroke 34:1987-1993.
Samoilova, M., J. Li, M.R. Pelletier, K. Wentlandt, Y. Adamchik, C.C. Naus and P.L. Carlen. (2003). Epileptiform activity in hippocampal slice cultures exposed chronically to bicuculline: increased gap junctional function and expression. J. Neurochem. 86:687-699.
Nakase, T., S. Fushiki, K. Willecke, G. Sohl, M. Theis and C.C. Naus. (2003). Neuroprotective role of astrocytic gap junctions in ischemic stroke. Cell Adhes. Commun. 10:413-417.
Frantseva, M.V., L. Lokarovtseva, C.C. Naus, P.L. Carlen and J.L. Perez Velazquez. (2002). Specific gap junctions enhance the neuronal vulnerability to brain traumatic injury. J. Neurosci. 22:644-653.
Naus, C.C. (2002). Gap junctions and tumour progression. Can. J. Physiol. Pharmacol. 80:136-141.
Ozog, M., R. Siushansian and C.C. Naus. (2002). Blocked gap junctional coupling increases glutamate-induced neurotoxicity in co-cultures of neurons and astrocytes. J. Neuropath. Exp. Neurol. 61:132-141.
Stout, C., J. Costantin, C.C. Naus and A. Charles. (2002). Intercellular calcium signaling in astrocytes via ATP release through connexin hemichannels; J. Biol.Chem. 277:10482-10488.
Ozog, M., J. Bechberger and C.C. Naus. (2002). Ciliary neurotrophic factor (CNTF) in combination with its soluble receptor (CNTFRa) increases connexin43 expression and suppresses growth of C6 glioma cell. Cancer Research 62:3544-3548. |
A,B,C,D: Decreased connexin43 expression results in increased infarct size and neuronal death (apoptosis green cells) following stroke injury in mice.
E: Connexin43 tagged with GFP enable us to visualize gap junction formation in live neurons.
F: Astrocytes in culture display localization of connexin43 at areas of intercellular contact.
G: A low molecular weight fluorescent dye (green) injected into a single cell (red) demonstrates the presence of gap junctions through the spread of the green dye.
H: Similar spread of a low molecular weight marker (neurobiotin) is also observed when a single neuron is injected in a brain slice.
I: The migration of new neurons can be followed as they are marked with bromodeoxyuridine in the developing cerebral cortex. |
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