Unique and shared functions of different connexins in mice

Background: Connexins are the protein subunits of intercellular gap junctio n channels. In mammals, they are encoded by a family of at least 15 genes, which show cell-type-specific but overlapping patterns of expression. Mice lacking connexin43 (Cx43) die postnatally from obstruction of the right ven tricular outflow tract of the heart. To discriminate between the unique and shared functions of Cx43, Cx40 and Cx32, we generated two 'knock-in' mouse lines, Cx43Kl32 and Cx43Kl40, in which the coding region of the Cx43 gene was replaced, respectively, by the coding regions of Cx32 or Cx40. Results: Heterozygous mutants were fertile and co-expressed the wild-type a nd the corresponding recombinant allele in all tissues analyzed. Heterozygo us Cx43Kl32, but not Cx43Kl40, mutant mothers were unable to nourish their pups to weaning age, possibly reflecting a defect in milk ejection. Homozyg ous mutant males were sterile because of extensive germ-cell deficiency. Th e ovaries of homozygous Cx43Kl32 neonates exhibited all stages of follicula r development and ovulation. The hearts of homozygous Cx43Kl32 neonates sho wed mild morphological defects, but the cardiac morphology of homozygous Cx 43Kl40 neonates was relatively normal. Spontaneous ventricular arrhythmias were observed in most Cx43Kl40 and some Cx43Kl32 mutant mice, suggesting in creased ventricular vulnerability in these mice. Conclusions: The postnatal lethality of Cx43-deficient mice was rescued in Cx43Kl32 or Cx43Kl40 mice, indicating that Cx43, Cx40 and Cx32 share at lea st some vital functions. On the other hand, Cx43Kl32 and Cx43Kl40 mice diff ered functionally and morphologically from each other and from wild-type mi ce. Thus, these connexins also have unique functions.