Connexins, Cell Proliferation and Second Messengers in the Crystalline Lens

Gap junctions are responsible for the direct coupling of cells that enables intercellular exchange of ions, small metabolites and second messengers. Lens epithelial cells are well coupled (Fig.1a) by connexin (Cx) channels that constitute the structural subunits of gap junctions.1,2 Surprisingly, epithelial cell proliferation during the early postnatal period (Fig.1b) was found to be profoundly influenced by the type of connexin subunit present in the gap junction channels between cells. The loss, or functional replacement, of Cx50 caused a significant decrease in the number of dividing cells during the first postnatal week, suggesting that Cx50-mediated communication was essential for peak mitosis to occur.3,4 In turn, the magnitude of coupling mediated by specific lens connexins can be differentially modulated by the same mitogenic signaling pathways that stimulate mitosis (Fig.1c). For example, we have previously shown that the mitogen activated protein kinase (MAPK) pathway specifically modulated Cx50, but not Cx46 in vitro, and that Cx50 mediated communication and MAPK signaling interacted in the regulation of lens development and homeostasis in vivo.4 More recently, we have seen that modulation of phosphoinositide 3-kinase (PI3K) activity also impacted cell proliferation and Cx50 mediated coupling in a similar manner to changes observed after perturbation of MAPK signaling. Integration of these observations has led us to the hypothesis that signal transduction drives mitosis in part through the generation of soluble second messengers that can permeate through gap junction channels, which are coordinately regulated by the same signal transduction pathways. To further test this hypothesis, we have Figure 1. Connexins, cell proliferation and second messengers in the lens. (a) Lens epithelial cells pass small fluorescent dyes through an extensive network of gap junction channels. (b) During early postnatal growth, mitotic activity is high across the entire epithelium as shown by EdU staining of an intact postnatal day 2 mouse lens. (c) Cx50 interacts with lens signal transduction pathways, including the MAPK and PI3K pathways that stimulate mitosis. (d) Schematic drawing of a cell pair based assay to measure cyclic nucleotide permeability through connexin channels.