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L.S. Musil, B. Boswell; Regulation of Lens Cell Communication by BMP Signaling . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5417.
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© ARVO (1962-2015); The Authors (2016-present)
Gap junction–mediated intercellular coupling (GJIC) is higher at the lens equator than at either pole, an asymmetry believed to be required for lens clarity. We have reported that primary cultures of embryonic chick lens epithelial cells (chDCDML) upregulate GJIC in response to either recombinant FGF (–1 or 2) or to serum–free medium conditioned by intact vitreous bodies, the major reservoir of diffusible factors (including FGF) for the lens equator in vivo (2001 J Cell Biol.). Removing FGF from vitreous body conditioned medium (VBCM) by heparin adsorption abolished its ability to increase GJIC. Because recombinant BMP –2 and 7 also increase GJIC, and VBCM contains BMP bioactivity, we investigated the potential role of BMP in vitreous–induced upregulation of GJIC.
chDCDMLs were cultured with VBCM with or without inhibitors of BMP–mediated signaling. After 48 h, GJIC was measured using the scrape–loading/dye transfer assay. BMP signaling was assessed by immunoblotting with an antibody specific for the phosphorylated (activated) form of smad1.
The ability of BMP2, BMP7, or VBCM to upregulate both smad1 activation and GJIC in cultured lens cells was blocked by noggin, a potent inhibitor of BMP –2, 4, and 7. In contrast, noggin had no effect on: (1) lens cell viability or proliferation; (2) calf serum–induced upregulation of GJIC; or (3) activation of ERK kinase by FGF. VBCM–stimulated GJIC (and smad1 phosphorylation) was also inhibited by anti–BMP antibodies and another highly specific blocker of BMP signaling, chordin. The ability of VBCM to upregulate GJIC in an ERK–independent manner was recapitulated by culturing chDCDMLs with a combination of FGF2 and BMP2 at concentrations that individually were insufficient to enhance GJIC.
Upregulation of GJIC in response to vitreous requires BMP in addition to FGF signaling. This is the first demonstration of a role for BMP in gap junction function in an ocular tissue, and of an obligatory interaction between BMP and FGF in regulating GJIC in any cell type. Because BMP and FGF signaling in vivo are highest at the lens equator, these results support a model in which both growth factors contribute to the gradient in lenticular gap junctional coupling needed for lens transparency.
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