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 fo r survival through early neonatal life. We examined electrical wave propaga tion in the left (LV) and right (RV) ventricles of isolated Cx43 null mutat ed (Cx43(-/-)), heterozygous (Cx43(+/-)), and wild-type (WT) embryos using high-resolution mapping of voltage-sensitive dye fluorescence. Consistent w ith the compensating presence of the other connexins, no reduction in propa gation velocity was seen in Cx43(-/-) ventricles at postcoital day (dpc) 12 .5 compared with WT or Cx43(+/-) ventricles. A gross reduction in conductio n velocity was seen in the RV at 15.5 dpc tin cm/second, mean [1 SE confide nce 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 tin RV , WT 8.4 [7.6 to 9.3], Cx43(+/-) 8.7 [8.1 to 9.3], and Cx43(-/-) 1.1 [0.1 t o 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 downreg ulation of Cx40, Cx40 and Cx45 mRNAs were detectable in ventricular homogen ates even at 17.5 dpc, probably accounting for the residual conduction func tion. 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 maint aining heart rhythm in postnatal life.