ProfessorCanada Research Chair in Gap Junctions in Neurological Disorders
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.
BSc (Queen’s University)
MSc (University of Western Ontario)
PhD (University of Western Ontario)
Selected Recent Publications:
- Sin, W.C., Q. Aftab, J. Bechberger, J. Leung, H. Chen and C.C. Naus. (2015). Astrocytes promote glioma invasion via the gap junction protein connexin43. Oncogene, in press. [Epub ahead of print Jul 13].
- Aftab, Q., W.C. Sin and C.C. Naus. (2015). Reduction in gap junction intercellular communication promotes glioma migration. Oncotarget 6:11447-11464. [Epub ahead of print March 19]
- Hong, X., W.C. Sin, A. Harris and C.C. Naus. (2015). Gap junctions modulate glioma invasion by direct transfer of microRNA. Oncotarget, 6:15566-15577. [Epub ahead of print May 4]
- Kolar K., M. Freitas-Andrade, J.F. Bechberger, H. Krishnan, G.S. Goldberg, C.C. Naus and W.C. Sin. (2015). Podoplanin: a new marker for gliosis in glioma and brain injury. J Neuropath Exp Neurol 74:64-74. (Cover of this Issue) [Epub ahead of print Dec 8]
- Freitas-Andrade, M. and C.C. Naus. (2015) Astrocytes in neuroprotection and neurodegeneration: the role of Connexin43 and Pannexin1. Neuroscience, in press. [Epub ahead of print Apr 23]
- Amtul, Z., S. Whitehead, R. Keeley, J. Bechberger, A. Fisher, R. McDonald, C. Naus, D. Munoz and D. Cechetto. (2015). Co-morbid rat model of ischemia and β-amyloid toxicity: Striatal and cortical degeneration. Brain Pathol. 25:24-32. [Epub ahead of print Apr 11, 2014]
- Rovegno, M., P. A. Soto, P.J. Sáez, C.C. Naus, J.C. Sáez and R. von Bernhardi. (2015). Connexin43 hemichannels mediate secondary cellular damage spread from the trauma zone to distal zones in astrocyte monolayers. Glia 63:1185-1199. [Epub ahead of print March 2]
- Nahta, R., F. Al-Mulla, R. Al-Temaimi, A. Amedei, R. Andrade-Vieira, S. Bay, D. Brown, G.M. Calaf, R.C. Castellino, K.A. Cohen-Solal, A. Colacci, N. Cruickshanks, P. Dent, R. Di Fiore, S. Forte, G.S. Goldberg, R.A. Hamid, H. Krishnan, D.W. Laird, A. Lasfar, P.A. Marignani, L. Memeo, C. Mondello, C.C. Naus, R. Ponce-Cusi, J. Raju, D. Roy, R. Roy, E. Ryan, H.K. Salem, I. Scovassi, N. Singh, M. Vaccari, R. Vento, J.VondraÅLček, M. Wade, J. Woodrick, W.H. Bisson. (2015). The Halifax Project: Assessing the Carcinogenic Potential of Low Dose Exposures to Chemical Mixtures in the Environment: Focus on the Cancer Hallmark of Evading Growth Suppression. Carcinogenesis 36 Suppl 1:S2-S18.
- Goodson, W.H., L. Lowe, D.O. Carpenter, M. Gilbertson, A.M. Ali, A. Lopez de Cerain Salsamendi, A. Lasfar, A. Carnero, A. Azqueta, A. Amedei, A.K. Charles, A.R. Collins, A. Ward, A.C. Salzberg, A. Colacci, A.-K. Olsen, A. Berg, B.J. Barclay, B.P. Zhou, C. Blanco-Aparicio, C. Baglole, C. Dong, C. Mondello, C.-W. Hsu, C.C. Naus, C. Yedjou, C.S. Curran, D.W. Laird, D.C. Koch, D.J. Carlin, D.W. Felsher, D. Roy, D. Brown, E. Ratovitski, E.P. Ryan, E. Corsini, E. Rojas, E.-Y. Moon, E. Laconi, F. Marongiu, F. Al-Mulla, F. Chiaradonna, F. Darroudi, F.L. Martin, F.J. Van Schooten, G.S. Goldberg, G. Wagemaker, G. Nangami, G. Rice, G.M. Calaf, G. Williams, G.T. Wolf, Gudrun Koppen50, G. Brunborg, H.K. Lyerly, H. Krishnan, H.A. Hamid, H. Yasaei, H. Sone, H. Kondoh, H.K. Salem, H.-Y. Hsu, H.H. Park, I. Koturbash, I.R. Miousse, I. Scovassi, J.E. Klaunig, J. Vondraalcek, J. Raju, J. Roman, J.P. Wise Sr., J.R. Whitfield, J. Woodrick, J. Christopher, J. Ochieng, J.F. Martinez-Leal, J. Weisz, J. Kravchenko, J. Sun, K.R. Prudhomme, K.B. Narayanan, K.A. Cohen-Solal, K. Moorwood, L. Gonzalez, L. Soucek, L. Jian, L.S. D’Abronzo, L.-T. Lin, L. Li, L. Gulliver, L.J. McCawley, L. Memeo, L. Vermeulen, L. Leyns, L. Zhang, M. Valverde, M. Khatami, M.F. Romano, M. Chapellier, M.A. Williams, M. Wade, M.H. Manjili, M. Lleonart, M. Xia, M.J. Gonzalez, M.V. Karamouzis, M. Kirsch-Volders, M. Vaccari, N.B. Kuemmerle, N. Singh, N. Cruickshanks, N. Kleinstreuer, N. van Larebeke, N. Ahmed, O. Ogunkua, P.K. Krishnakumar, P. Vadgama, P.A. Marignani, P.M. Ghosh, P. Ostrosky-Wegman, P. Thompson, P. Dent, P. Heneberg, P. Darbre, P. S. Leung, P. Nangia-Makker, Q. Cheng, R.B. Robey, R. Al-Temaimi, R. Roy, R. Andrade-Vieira, R.K. Sinha, R. Mehta, R. Vento, R. Di Fiore, R. Ponce-Cusi, R. Dornetshuber-Fleiss, R. Nahta, R.C. Castellino, R. Palorini, R.A. Hamid, S.A. Langie, S. Eltom, S.A. Brooks, S. Ryeom, S.S. Wise, S.N. Ba, S. Harris, S. Papagerakis, S. Romano, S. Pavanello, S. Eriksson, S. Forte, S.C. Casey, S. Luanpitpong, T.-J. Lee, T. Otsuki, T. Chen, T. Massfelder, T. Sanderson, T. Guarnieri, T. Hultman, V. Dormoy, V. Odero-Marah, V. Sabbisetti, V. Maguer-Satta, W.K. Rathmell, W. Engstroanm, W.K. Decker. (2015). Assessing the carcinogenic potential of low dose exposures to chemical mixtures in the environment: The challenge ahead. Carcinogenesis 36 Suppl 1:S254-96.
- Decrock E., M. De Bock, N. Wang, G. Bultynck, C. Giaume, C.C. Naus, C.R Green, L. Leybaert. (2015). Connexin and pannexin signaling pathways, an architectural blueprint for CNS physiology and pathology? Cellular and Molecular Life Sciences 72:2823-2851. [Epub ahead of print June 29]
- Le, H.T., W.C. Sin, S. Lozinsky, J. Bechberger, J.L. Vega, X.Q. Guo, J.C. Saez, and C.C. Naus. (2014). Gap junction intercellular communication mediated by connexin43 in astrocytes is essential for their resistance to oxidative stress. J. Biol. Chem. 289:1345-1354. [Epub 2013 Dec 3]
- Simonsen, K., D. Moerman and C.C. Naus. (2014). “Innexins in C. elegans”. Frontiers in Physiology: Frontiers in Membrane Physiology and Membrane Biophysics 5:40, 1-6.
- Bond, S. and C.C. Naus. (2014). The pannexins: past and present. Frontiers in Physiology: Frontiers in Membrane Physiology and Membrane Biophysics 5:58, 1-24.
- Falk, L., M. Dang-Lawson, J.L. Vega Pizzaro, F. Pournia, K. Choi, C. Jang, C.C. Naus and L. Matsuuchi. (2014). Mutations of Cx43 that effect B cell spreading in response to BCR signaling. Biology Open 3:185-194. [Epub 2014 Jan 14]
- Machtaler, S., K. Choi, M. Dang-Lawson, L. Falk, F. Pournia, C.C. Naus and L. Matsuuchi. (2014). The role of the gap junction protein connexin43 in B lymphocyte motility and migration. FEBS Lett. 588:1249-1258. [Epub 2014 Jan 20]
- Amtul, Z., S. Nikolova, L. Gao, R.J. Keeley, J. Bechberger, A. Fisher, R. Bartha, D.G. Munoz, R.J. McDonald, C.C. Naus, J.M. Wojtowicz, V. Hachinski and D.F. Cechetto. (2014). Comorbid Aβ toxicity and stroke: hippocampal atrophy, pathology, and cognitive deficit. Neurobiology of Aging 35:1605-14. [Epub 2014 Jan 8]
- Stewart, M.K., I. Plante, J.F. Bechberger, C.C. Naus and D.W. Laird. (2014). Mammary gland specific knockdown of the physiological surge in Cx26 during pregnancy retains normal mammary gland development and function. PLOS One 9(7): e101546. doi:10.1371/journal.pone.0101546.
- Abudara, V., J. Bechberger, M. Freitas-Andrade, M. De Bock, N. Wang, G. Bultynck, C.C. Naus, L. Leybaert and C. Giaume. (2014). The mimetic peptide Gap19 inhibits connexin 43 hemichannels without altering gap junctional communication in astrocytes. Frontiers in Cellular Neuroscience, Oct 21;8:306. doi: 10.3389/fncel.2014.00306.
- Le Vasseur, M., J. Lelowski, J.F. Bechberger, W.C. Sin and C.C. Naus. (2014). Pannexin 2 is a ubiquitous gap junction protein with cytoplasmic localization. Frontiers in Cellular Neuroscience, Nov 25;8:392. doi: 10.3389/fncel.2014.00392.
- Matsuuchi, L. and C.C. Naus. (2013). Gap junction proteins on the move: Connexins, the cytoskeleton and migration. Biochim Biophys Acta – Biomembranes 1828:94–108. [Epub 2012 May 18]
- Chen, V.C., J.W. Gouw, C.C. Naus and L. Foster. (2013). Connexin multisite phosphorylation: Mass spectrometry-based proteomics fills the gap. Biochim Biophys Acta – Biomembrances 1828:23–34. [Epub 2012 Mar 6]
- Giaume, C. and Naus, C.C. (2013). Gap junctions between glia. WIREs Membr Transp Signal 2:133–142. doi: 10.1002/wmts.87.
- Kozoriz, M.G., S. Lai, J.L. Vega, J.C. Saez, W.C. Sin, J.F. Bechberger and C.C. Naus. (2013). Cerebral ischemic injury is enhanced in a model of oculodentodigital dysplasia. Neuropharmology 75:549-556. [Epub 2013 May 31]
- Gielen, P.R., Q. Aftab , N. Maa, V.C. Chen, X. Hong, S. Lozinsky, C.C. Naus and W.C. Sin. (2013). Cx43 confers Temozolomide resistance in human glioma cells by modulating the mitochondrial apoptosis pathway. Neuropharmology 75:539-548. [Epub 2013 May 18]
- Mancuso, M. S. Leonardi, P. Giardullo, E. Pasquali, M. Tanori, I. De Stefano, A. Casciati, C.C. Naus, S. Pazzaglia, and A. Saran. (2013). Oncogenic radiation abscopal effects in vivo: Interrogating mouse skin. Int J Radiat Oncol Biol Phys 86:993-999. [Epub 2013 June 5]
- Giaume, C., L. Leybaert, C.C. Naus and J.C. Saez. (2013). Connexin and pannexin hemichannels in brain glial cells: properties, pharmacology and roles. Frontiers in Pharmacology 4:88, 1-17.
- Decrock E., D.V. Krysko, M. Vinken, A. Kaczmarek, G. Crispino, M. Bol, N. Wang, M. De Bock, E. De Vuyst, C.C. Naus, V. Rogiers, P. Vandenabeele, C. Erneux, F. Mammano, G. Bultynck and L. Leybaert. (2012). Transfer of IP3 through gap junctions is critical, but not sufficient, for the spread of apoptosis. Cell Death and Differentiation 19:947-957. [Epub 2011 Nov 25]
- Lamiche, C. J. Clarhaut, P.O. Strale, S. Crespin, N. Pedretti, F.X. Bernard, C.C. Naus, V. Chen, L. Foster, N. Defamie, M. Mesnil, F. Debais and L. Cronier. (2012). The gap junction protein Cx43 is involved in the bone-targeted metastatic behaviour of human prostate cancer cells. Clinical & Experimental Metastasis 29:111-122. [Epub 2011 Nov 12].
- Bao, B.A., C.P.K. Lai, C.C. Naus and J.R. Morgan. (2012). Pannexin1 drives multicellular aggregate compaction via a signaling cascade that upregulates cytoskeletal function. J. Biol. Chem. 287:8407-8416. [Epub 2012 Jan 20].
- Bond, S.R. and C.C. Naus. (2012). Restriction free cloning – http://www.rf-cloning.org. Nucleic Acid Research 40(W1):W209-W213. [Epub 2012 May 8]
- Bond, S.R., N. Wang, L. Leybeart and C.C. Naus. (2012). Pannexin 1 ohnologs in the teleost lineage. J. Membr. Biol., 245:483-493. [Epub 2012 Aug 26].
- Theodoric, N., J.F. Bechberger, C.C. Naus and W.C. Sin. (2012). Role of gap junction protein Connexin43 in astrogliosis induced by brain injury. PLoS One, 7(10):e47311. doi: 10.1371/journal.pone.0047311. [Epub 2012 Oct 23].
- Chen, V.C., A.R. Kristensen, L.J. Foster and C.C. Naus. (2012). The association of Cx43 with E3 ubiquitin ligase TRIM21 reveals a mechanism for gap junction phosphodegron control. Journal Proteome Research 11:6134-6146. [Epub 2-12 Nov 8]
- Wang, N., E. De Vuyst, R. Ponsaerts, K. Boengler, N. Palacios-Prado, J. Wauman, C.P.K. Lai, M. De Bock, M. De Bock, E. Decrock, M. Bol, M. Vinken, V. Rogiers, J. Tavernier, W.H. Evans, C.C. Naus, F. Bukauskas, K.R. Sipidio, G. Heusch, R. Schulz, G. Bultynck and L. Leybaert. (2013). Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury. Basic Research in Cardiology 108:309. [Epub 2012 Nov 8]
- Orellana, J.A., K.F. Shoji, V. Abudara, P. Ezan, E. Amigou, P.J. Saez, J.X. Jiang, C.C. Naus, J.C. Saez and C. Giaume. (2011). Amyloid beta-induced death in cultured neurons involves glial and neuronal hemichannels. J. Neurosci. 31:4962-4977.
- Orellana, J.A., N. Frogeer, P. Ezan, M.V.L. Bennett, C.C. Naus, C. Giaume and J.C. Saez. (2011). ATP and gluatmate released via astroglial connexin43 hemichannels mediate neuronal death through activation of pannexin 1 hemichannels. J. Neurochem. 18:826-840. [Epub 2011 Mar 7].
- Sosinsky,G., D. Boassa, H. Duffy, R. Dermietzel, D. Laird, B. MacVicar, C.C. Naus, S. Penuela, E. Scemes, D. Spray, R.J. Thompson, H. Zhao and G. Dahl. (2011). Pannexin channels are not gap junction hemichannels – Commentary. Channels 5:193-197. [Epub 2011 May 1].
- Mancuso, M., S. Leonardi, E. Pasquali, S. Rebessi, M. Tanori, P. Giardullo, F. Borra, S. Pazzaglia, C.C. Naus, V. Di Majo and A. Saran. (2011). Interplay of ATP and Connexin43 in abscopal radiation tissue damage and oncogenesis in vivo. Oncogene 30:4601-4608. [Epub 2011 May 23]
- Machtaler, S., C. Jang, K. Choi, C.C. Naus and L. Matsuuchi. (2011). Expression of the gap junction protein Cx43 influences B lympohocyte adhesion and cell spreading. J. Cell Sci. 124:2611-2621. [Epub 2011 Jul 12].
- Bond, S.R., A.T. Lau, R. Bhalla, S. Penuela, A.V. Sampaio, T.M. Underhill, D.W. Laird, and C.C. Naus. (2011). Pannexin3 is a novel target for Runx2 expressed by mature osteoblasts and hypertrohic chondrocytes. J. Bone Mineral Res. 26:2911-2922. [Epub 2011 Sept 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]
- 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]
- Naus, C.C. and D.W. Laird. (2010). Implications and challenges of connexin connections in cancer. Nature Reviews Cancer 10:435-441.
- 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. 110:589-597.
- 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 29:5712-5723. [Epub 2010 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. 285:31107-31119. [Epub 2010 July 28].