Cataracts affect the vision of an estimated 20.5 million Americans. In previous investigations, we developed a serum-free primary embryonic chick lens cell culture system (DCDMLs) and used it to show that fibroblast growth factor (FGF), at levels available to the lens equator in vivo, upregulates both gap junction-mediated intercellular communication and expression of markers of epithelial-tofiber differentiation. More recently, we have demonstrated that the ability of FGF to promote these processes is completely dependent on lens-derived bone morphogenic protein (BMP) -4 and/or 7. Studies in transgenic mice overexpressing a BMP inhibitor in the lens support the hypothesis that normal lens development and function reguires both the FGF and BMP signaling pathways. Another ocular growth factor, TGFj3, is involved in the development of anterior subcapsular cataracts (ASC). Preliminary results shown here demonstrate that TGFj3 is the first physiologically relevant growth factor that perturbs lens cell gap junctions in an manner dependent on the concentration of FGF. The goals of the proposed studies are: (1) To define the signaling mechanisms whereby TGFj3 perturbs gap junction-mediated intercellular communication between lens cells, and (2) To elucidate the in vivo role of BMP4 in secondary fiber differentiation in transgenic mice. This abstract was revised to match the two year length of this award.
Cataracts are the leading cause of blindness world-wide, and are responsible for ~60% of all vision-related Medicare expenditures. The goal of this research is to understand how two processes required for lens transparency, gap junction-mediated intercellular communication and formation of crystallin-rich lens fiber cells, are regulated, and how they are disrupted by cataract-associated changes in growth factor signaling and/or mutation. This information will help develop therapies to combat the vision-destroying effects of cataract and of the most common complication of cataract surgery, posterior capsule opacification.
|Boswell, Bruce A; Musil, Linda S (2015) Synergistic interaction between the fibroblast growth factor and bone morphogenetic protein signaling pathways in lens cells. Mol Biol Cell 26:2561-72|
|Musil, Linda S (2012) Primary cultures of embryonic chick lens cells as a model system to study lens gap junctions and fiber cell differentiation. J Membr Biol 245:357-68|
|Donaldson, Paul J; Musil, Linda S; Mathias, Richard T (2010) Point: A critical appraisal of the lens circulation model--an experimental paradigm for understanding the maintenance of lens transparency? Invest Ophthalmol Vis Sci 51:2303-6|
|Boswell, Bruce A; VanSlyke, Judy K; Musil, Linda S (2010) Regulation of lens gap junctions by Transforming Growth Factor beta. Mol Biol Cell 21:1686-97|
|Vanslyke, Judy K; Naus, Christian C; Musil, Linda S (2009) Conformational maturation and post-ER multisubunit assembly of gap junction proteins. Mol Biol Cell 20:2451-63|
|Boswell, Bruce A; Le, Anh-Chi N; Musil, Linda S (2009) Upregulation and maintenance of gap junctional communication in lens cells. Exp Eye Res 88:919-27|
|Boswell, Bruce A; Overbeek, Paul A; Musil, Linda S (2008) Essential role of BMPs in FGF-induced secondary lens fiber differentiation. Dev Biol 324:202-12|
|Boswell, Bruce A; Lein, Pamela J; Musil, Linda S (2008) Cross-talk between fibroblast growth factor and bone morphogenetic proteins regulates gap junction-mediated intercellular communication in lens cells. Mol Biol Cell 19:2631-41|
|VanSlyke, Judy K; Musil, Linda S (2005) Cytosolic stress reduces degradation of connexin43 internalized from the cell surface and enhances gap junction formation and function. Mol Biol Cell 16:5247-57|
|VanSlyke, Judy K; Musil, Linda S (2003) Degradation of connexins from the plasma membrane is regulated by inhibitors of protein synthesis. Cell Commun Adhes 10:329-33|