Regulation of lens gap junctions by Transforming Growth Factor beta.
Gap junction-mediated intercellular communication (GJIC) is essential for the proper function of many organs, including the lens. GJIC in lens epithelial cells is increased by FGF in a concentration-dependent process that has been linked to the intralenticular gradient of GJIC required for lens transparency. Unlike FGF, elevated levels of TGF-beta are associated with lens dysfunction. We show that TGF-beta1 or -2 up-regulates dye coupling in serum-free primary cultures of chick lens epithelial cells (dissociated cell-derived monolayer cultures [DCDMLs]) via a mechanism distinct from that utilized by other growth factors. Remarkably, the ability of TGF-beta and of FGF to up-regulate GJIC is abolished if DCDMLs are simultaneously exposed to both factors despite undiminished cell-cell contact. This reduction in dye coupling is attributable to an inhibition of gap junction assembly. Connexin 45.6, 43, and 56-containing gap junctions are restored, and intercellular dye coupling is increased, if the activity of p38 kinase is blocked. Our data reveal a new type of cross-talk between the FGF and TGF-beta pathways, as well as a novel role for TGF-beta and p38 kinase in the regulation of GJIC. They also provide an explanation for how pathologically increased TGF-beta signaling could contribute to cataract formation.
Boswell
Bruce A
BA
Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR 97239, USA.
VanSlyke
Judy K
JK
Musil
Linda S
LS
D000818:Animals; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D002642:Chick Embryo; D017630:Connexins; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism / Q000502:physiology; D017629:Gap Junctions / Q000378:metabolism* / Q000502:physiology; D007908:Lens, Crystalline / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D017630:Connexins; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C082920:connexin 45; D005346:Fibroblast Growth Factors