A novel role for FGF and extracellular signal–regulated kinase in gap junction–mediated intercellular communication in the lens

Abstract

Gap junction–mediated intercellular coupling is higher in the equatorial region of the lens than at either pole, a property believed to be essential for lens transparency. We show that fibroblast growth factor (FGF) upregulates gap junctional intercellular dye transfer in primary cultures of embryonic chick lens cells without detectably increasing either gap junction protein (connexin) synthesis or assembly. Insulin and insulin-like growth factor 1, as potent as FGF in inducing lens cell differentiation, had no effect on gap junctions. FGF induced sustained activation of extracellular signal–regulated kinase (ERK) in lens cells, an event necessary and sufficient to increase gap junctional coupling. We also identify vitreous humor as an in vivo source of an FGF-like intercellular communication-promoting activity and show that FGF-induced ERK activation in the intact lens is higher in the equatorial region than in polar and core fibers. These findings support a model in which regional differences in FGF signaling through the ERK pathway lead to the asymmetry in gap junctional coupling required for proper lens function. Our results also identify upregulation of intercellular communication as a new function for sustained ERK activation and change the current paradigm that ERKs only negatively regulate gap junction channel activity.

Restoration of Functional Gap Junctions through Internal Ribosome Entry Site-Dependent Synthesis of Endogenous Connexins in Density-Inhibited Cancer Cells

“…Scrape-loading and dye transfer assay for gap junction intercellular communication. BxPC-3 cells were assessed for gap junction-mediated intercellular communication using a protocol adapted from that of Le and Musil (27,28). Cells were plated on glass coverslips in 35-mm-diameter dishes (6 ϫ 10 5 cells/ dish) and grown for 4 days to confluence.…”

Gap junctions relay FGF8‐mediated right‐sided repression of Nodal in rabbit

“…In chick lens cultures, FGF controls the opening status of gap junctions (GJs) and enhances GJC (Le and Musil, 2001). In chick limb bud cultures, application of FGF4/8 augments expression of the GJ gene connexin 43 (Cx43; Makarenkova et al, 1997).…”

The cataract-inducing S50P mutation in Cx50 dominantly alters the channel gating of wild-type lens connexins

“…Recent studies have revealed that connexin diversity plays an integral role in the correct development and function of the mammalian lens, contributing to changes in channel gating and permeation (Gao et al, 2004;Le and Musil, 2001;MartinezWittinghan et al, 2003;Rong et al, 2002;White, 2003). In the past, different Cx50 variants have been described in the development of several distinct types of dominant cataract in mice (Chang et al, 2002;Graw et al, 2001;Steele et al, 1998;Xia et al, 2006a).…”