Our laboratoryis interested in examining mutations in Cx26, Cx30 and Cx43 that lead to hearing loss, various skin diseases and oculodentodigital dysplasia (ODDD). Interestingly, a number of loss-of-function point mutations in Cx26 have been identified that result in only hearing loss while others exhibit putative trans-dominant phenotypes resulting in both hearing loss and various forms of human skin disease. In our laboratory, mutant connexins are expressed and characterized in a number of well understood cell lines as well as in tissue-relevant cells that are capable of undergoing differentiation. Transgenic mice that mimic human connexin-linked diseases are also being routinely used.
In 2003, the first human disease found to be linked to the gene encoding Cx43 (GJA1) was oculodentodigital dysplasia (ODDD). ODDD is primarily an autosomal-dominant human disorder where patients commonly display symptoms of congenital craniofacial deformities, ocular defects, enamel loss and fused digits. To date, there are over sixty known Cx43 gene mutations linked to ODDD, with the majority clustered in the N-terminal two-thirds of the Cx43 polypeptide sequence. The consequences of these mutations on Cx43 function are being investigated in reference cell systems and organotypic models such as the epidermis. These studies are being complemented with genetically-modified mouse models that harbor Cx43 mutants and mimic the human ODDD disease. In recent years we have also established several bench-to-bedside studies involving patient samples obtained from around the world. This approach has led to the establishment of a repository of ODDD patient samples and established cell lines that can be further used to explore the etiology of ODDD. Once mechanistic information is known as to how mutant connexins cause disease, long-term goals include developing strategies to compensate for cellular defects caused by these mutants.
M.K.G. Stewart, X.-Q, Gong, K.J. Barr, D. Bai, G.I. Fishman and D.W. Laird (2013) “Mammary gland defects as revealed by genetically-modified mice harboring an oculodentodigital dysplasia-linked Cx43 mutant” Biochemical Journal 449: 401-213.
R. Lorentz, Q. Shao, T. Huang, G.I. Fishman and D.W. Laird(2012) “Characterization of gap junction proteins in the bladder of Cx43 mutant mouse models of oculodentodigital dysplasia” Journal of Membrane Biology 245: 345-355.
Q. Shao, Q. Liu, R. Lorentz, X. Gong, D. Bai, G. Shaw* and D.W. Laird* (2012) “Structure and functional studies of N-terminal Cx43 mutants linked to oculodentodigital dysplasia” Molecular Biology of the Cell 23: 3312-3321. *Co-senior authors.
J.M. Churko, J. Kelly, A. McDonald, J. Lee, J. Sampson, D. Bai, and D.W. Laird (2012) “Mutant Cx43 enhances keratinocyte proliferation without impacting keratinocyte migration” Experimental Dermatology 21: 612-618. *Image selected for the cover.
J.M. Churko, Q. Shao, X-Q Gong, K. Swoboda, D. Bai, J. Sampson, D.W. Laird (2011) “Human dermal fibroblasts derived from oculodentodigital dysplasia patients suggest that patients have wound healing defects” Human Mutation 32: 456-466.
J.M. Churko, J. Chan, Q. Shao and D.W. Laird (2011) “The G60S connexin43 mutant regulates hair growth and hair fiber morphology in a mouse model of human oculodentodigital dysplasia” Journal of Investigative Dermatology 131:2197-2204.
E. Tsui, K.A. Hill, A.M. Laliberte, D. Paluzzi, I. Kisilevsky, Q. Shao, G.J. Heathcote, D.W. Laird, G.M. Kidder and C.M.L Hutnik (2011) “Ocular pathology relevant to glaucoma in a GjaJrt/+ mouse model of human oculodentodigital dysplasia” Investigative Ophthalmology and Visual Science 52:3539-3547.
J.M. Churko, S. Langlois, X. Pan, Q. Shao and D.W. Laird (2010) “The potency of the fs260 Cx43 mutant to impair keratinocyte differentiation is distinct from other disease-linked Cx43 mutants” Biochemical Journal 429: 473-483.
K. Toth, Q. Shao and D.W. Laird (2010) “Decreased levels of Cx43 gap junctions result in ameloblast dysregulation and enamel hypoplasia in Gja1Jrt/+ mice” Journal of Cellular Physiology 223:601-609.
D. Tong, D. Colley, R. Thoo, T.Y. Li, I. Plante, D.W. Laird, D. Bai and G.M. Kidder (2009) “Oogenesis defects in a mutant mouse model of oculodentodigital dysplasia” Disease Models and Mechanisms 3-4:157-167. Featured Article “In this Issue”
D. Tong, X. Lu, H.X. Wang, I. Plante, E. Lui, D.W. Laird, D. Bai and G.M. Kidder (2009) “A dominant loss-of-function GJA1 (Cx43) mutant impairs parturition in the mouse” Biology of Reproduction 80:1099-1106.
E. McLachlan, I. Plante, Q. Shao, D. Tong, G.M. Kidder, S.M. Bernier and D.W. Laird (2008) “ODDD-linked Cx43 mutants reduce endogenous Cx43 expression and function in osteoblasts and inhibit late stage differentiation” Journal of Bone and Mineral Research 23:928-938.
I. Plante and D.W. Laird (2008) “Decreased levels of connexin43 result in impaired development of the mammary gland in a mouse model of oculodentodigital dysplasia” Developmental Biology 318: 312-322. (Image selected for the Journal cover of the June edition)
J.L. Manias, I. Plante, X.-Q. Gong, Q. Shao, J. Churko, D. Bai and D.W. Laird (2008) “Fate of Cx43 in cardiac tissue harbouring a disease-linked Cx43 mutant” Cardiovascular Research 80:385-395
D.W. Laird (2008) “Closing the gap on autosomal dominant connexin-26 and connexin-43 mutants linked to human disease” Journal of Biological Chemistry 283:2997-3001.
X.-Q. Gong, Q. Shao, S. Langlois, D. Bai*, and D.W. Laird* (2007) “Differential potency of dominant negative connexin43 mutants in oculodentodigital dysplasia” Journal of Biological Chemistry 282:19190-19202 *co-senior authors
T. Thomas, Q. Shao and D.W. Laird (2007) “Differentiation of organotypic epidermis in the presence of skin disease-linked dominant-negative Cx26 mutants and knock-down Cx26” Journal of Membrane Biology 217: 93-104
D.W. Laird (2006) “Life Cycle of Connexin in Health and Disease” Biochemical Journal 394:527-543 Second most highly cited paper that year of any papers published by the Biochemical Journal as noted at the 2008 Editorial Board meeting.
X.-Q. Gong, Q. Shao, C.S. Lounsbury, D. Bai and D.W. Laird (2006) “Functional characterization of a GJA1 frame-shift mutation causing oculodentodigital dysplasia and palmoplantar keratodermas” Journal of Biological Chemistry281: 31801-31811