Regulation of Gap Junction Protein (Connexin) Genes and Function in Differentiating ES Cells

Gap junctions are specialized cell-cell junctions that directly link the cytoplasm of neighboring cells. They mediate the direct transfer of low molecular weight (<1000 D) metabolites and ions, including second messengers such as cyclic adenosine monophosphate (cAMP), inositol trisphosphate, and Ca²⁺ between adjacent cells. Therefore, gap junctional intercellular communication is considered to play an important role in the control of cell growth, differentiation, morphogenesis, and the maintenance of homeostasis. Gap junctions are composed of oligomeric proteins consisting of 6 subunits called connexins (Cxs) that are coded for by a multigene family (1 ,2 ). Thus far, more than 14 different Cxs have been cloned in rodent genes. The expression of each Cx has organ and cell-type specificity and is developmentally controlled. During the cardiomyocytic differentiation of embryonic stem (ES) cells in vitro, the expression of multiple Cxs is differentially regulated, and gap junctional intercellular communication is modulated (3 –5 ).