Null mutation of connexin43 causes slow propagation of ventricular activation in the late stages of mouse embryonic development.
Connexin43 (Cx43) is the principal connexin isoform in the mouse ventricle, where it is thought to provide electrical coupling between cells. Knocking out this gene results in anatomic malformations that nevertheless allow for survival through early neonatal life. We examined electrical wave propagation in the left (LV) and right (RV) ventricles of isolated Cx43 null mutated (Cx43(-/-)), heterozygous (Cx43(+/)(-)), and wild-type (WT) embryos using high-resolution mapping of voltage-sensitive dye fluorescence. Consistent with the compensating presence of the other connexins, no reduction in propagation velocity was seen in Cx43(-/-) ventricles at postcoital day (dpc) 12.5 compared with WT or Cx43(+/)(-) ventricles. A gross reduction in conduction velocity was seen in the RV at 15.5 dpc (in cm/second, mean [1 SE confidence interval], WT 9.9 [8.7 to 11.2], Cx43(+/)(-) 9.9 [9.0 to 10.9], and Cx43(-/-) 2.2 [1.8 to 2.7; P<0.005]) and in both ventricles at 17.5 dpc (in RV, WT 8.4 [7.6 to 9.3], Cx43(+/)(-) 8.7 [8.1 to 9.3], and Cx43(-/-) 1.1 [0.1 to 1.3; P<0.005]; in LV, WT 10.1 [9.4 to 10.7], Cx43(+/)(-) 8.3 [7.8 to 8.9], and Cx43(-/-) 1.7 [1.3 to 2.1; P<0.005]) corresponding with the downregulation of Cx40. Cx40 and Cx45 mRNAs were detectable in ventricular homogenates even at 17.5 dpc, probably accounting for the residual conduction function. Neonatal knockout hearts were arrhythmic in vivo as well as ex vivo. This study demonstrates the contribution of Cx43 to the electrical function of the developing mouse heart and the essential role of this gene in maintaining heart rhythm in postnatal life.
Vaidya
D
D
Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
Tamaddon
H S
HS
Lo
C W
CW
Taffet
S M
SM
Delmar
M
M
Morley
G E
GE
Jalife
J
J
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000196:embryology / Q000503:physiopathology*; D018780:Body Surface Potential Mapping; D002304:Cardiac Pacing, Artificial; D018031:Connexin 43 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000379:methods; D022062:Electrophysiologic Techniques, Cardiac; D005456:Fluorescent Dyes; D006329:Heart Conduction System / Q000503:physiopathology; D006339:Heart Rate; D006352:Heart Ventricles / Q000737:chemistry / Q000196:embryology / Q000503:physiopathology*; D006579:Heterozygote; D006720:Homozygote; D066298:In Vitro Techniques; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D055095:Optics and Photonics; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D018754:Ventricular Dysfunction / Q000196:embryology / Q000235:genetics / Q000503:physiopathology*; D014741:Video Recording; D000097003:Gap Junction alpha-5 Protein
D018031:Connexin 43; D017630:Connexins; D005456:Fluorescent Dyes; D012333:RNA, Messenger; D000097003:Gap Junction alpha-5 Protein; C082920:connexin 45