Doubly mutant mice, deficient in connexin32 and -43, show normal prenatal development of organs where the two gap junction proteins are expressed in the same cells

The connexins are a family of proteins that form the intercellular membrane channels of gap junctions. Genes encoding 13 different rodent connexins ha ve been cloned and characterized to date. Connexins vary both in their dist ribution among adult cell types and in the properties of the channels that they form. In order io explore the functional significance of connexin dive rsity, several mouse connexin-encoding genes have been disrupted by homolog ous recombination in embryonic stem cells. Although those experiments have illuminated specific physiological roles for individual connexins, the resu lts have also raised the possibility that connexins may functionally compen sate for one another in cells where they are coexpressed. In the present st udy, we have tested this hypothesis by interbreeding mice carrying null mut ations in the genes (Gjb 1 and Gja 1) encoding connexin32 (beta(1) connexin ) and connexin43 toll connexin), respectively. We found that fetuses tackin g both connexins survive to term but, as expected, the pups die soon therea fter from the cardiac abnormality caused by the absence of connexin43. A su rvey of the major organ systems of the doubly mutant fetuses, including the thyroid gland, developing teeth, and limbs where these two connexins are c oexpressed, failed to reveal any morphological abnormalities not already se en in connexin43 deficient fetuses. Furthermore, the production of thyroxin e by doubly mutant thyroids was confirmed by immunocytochemistry. We conclu de that, at least as far as the prenatal period is concerned, the normal de velopment of those three organs in fetuses lacking connexin43 cannot simply be explained by the additional presence of connexin32 and vice-versa. Eith er gap junctional coupling is dispensable in embryonic and fetal cells in w hich these two connexins are coexpressed, or coupling is provided by yet an other connexin when both are absent. (C) 1999 Wiley-Liss, Inc.