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A Dominant Loss-of-Function GJA1 (Cx43) Mutant Impairs Parturition in the Mouse

Dan Tong, University of Western Ontario
Xuerong Lu, University of Western Ontario
Hong-Xing Wang, University of Western Ontario
Isabelle Plante, University of Western Ontario
Ed Lui, University of Western Ontario
Dale W. Laird, University of Western Ontario
Donglin Bai, University of Western Ontario
Gerald M. Kidder, University of Western Ontario

Abstract

Expression of GJA1 (commonly known as connexin43 or Cx43), a major myometrial gap junction protein, is upregulated before the onset of delivery, suggesting an essential role for Cx43-mediated gap junctional intercellular communication (GJIC) in normal uterine contraction during parturition. To determine how a disease-linked Cx43 mutation affects myometrial function, we studied a mutant mouse model carrying an autosomal dominant mutation (Gja1Jrt) in the gene encoding Cx43 that displays features of the human genetic disease oculodentodigital dysplasia. We found that Cx43 level, specifically the phosphorylated species of the protein, is significantly reduced in the myometrium of the mutant mice (Gja1Jrt/+), as revealed by Western blotting and immunostaining. Patch-clamp electrophysiological measurements demonstrated that coupling between myometrial smooth muscle cells is reduced to <15% of wild-type, indicating that the mutant protein acts dominantly on its wild-type counterpart. The phosphorylated species of Cx43 in the mutant myometrium failed to increase prior to parturition as well as in response to exogenous estrogen. Correspondingly, in vitro experiments with uterine strips revealed weaker contraction of the mutant myometrium and reduced responsiveness to oxytocin, providing an explanation for the prolonged gestation and presence of suffocated fetuses in the uteri that were observed in some of the mutant mice. We conclude that the Gja1Jrt mutation has a dominant-negative effect on Cx43 function in the myometrium, severely reducing GJIC, leading to impaired parturition.

Suggested Citation

Dan Tong, Xuerong Lu, Hong-Xing Wang, Isabelle Plante, Ed Lui, Dale W. Laird, Donglin Bai, and Gerald M. Kidder. "A Dominant Loss-of-Function GJA1 (Cx43) Mutant Impairs Parturition in the Mouse" Biology of Reproduction 80.6 (2009): 1099-1106.
Available at: http://works.bepress.com/ed_lui/4