A dominant loss-of-function GJA1 (Cx43) mutant impairs parturition in the mouse.
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 (Gja1(Jrt)) 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 (Gja1(Jrt)/+), 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 Gja1(Jrt) mutation has a dominant-negative effect on Cx43 function in the myometrium, severely reducing GJIC, leading to impaired parturition.
Tong
Dan
D
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, Ontario, Canada.
Lu
Xuerong
X
Wang
Hong-Xing
HX
Plante
Isabelle
I
Lui
Ed
E
Laird
Dale W
DW
Bai
Donglin
D
Kidder
Gerald M
GM
D000818:Animals; D018031:Connexin 43 / Q000235:genetics* / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D017629:Gap Junctions / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D009215:Myometrium / Q000378:metabolism; D036801:Parturition; D011247:Pregnancy; D011270:Pregnancy, Animal; D014590:Uterine Contraction
D018031:Connexin 43; D004967:Estrogens