Abstract
Lens major intrinsic protein (MIP), exclusive to the vertebrate lens, otherwise known as MIP26 and Aquaporin 0, is abundantly expressed as a lens fiber membrane protein. Although relatively less efficient compared with other aquaporins, MIP is suggested to function as a water channel, as an adhesion molecule, and is required for lens transparency. Because MIP is specifically expressed in lens fiber cells, we investigated in this study the activation of Mip expression after triggering differentiation of rat lens epithelia explants by fibroblast growth factor (FGF)-2. Here, we show that Mip expression in the lens cells is regulated by FGF-2. Using Real time PCR we demonstrate that endogenous Mip levels in the explants were up-regulated upon FGF-2 stimulation, in a concentration-dependent manner. Up-regulation of Mip at the transcriptional level was simultaneous with the activation of the FGF down-stream signaling components, ERK1/2 and JNK. Specific inhibitors, UO126 for ERK1/2 and SP600125 for JNK, abrogated Mip expression in response to FGF-2 in the explants. This inhibition pattern was recapitulated in reporter assays for transfection of the rat lens epithelia explants, driven by the Mip promoter (-1648/+44). Our studies show that ERK1/2 and JNK signaling pathways are required for Mip expression in lens epithelia explants induced to differentiate by FGF-2.
Highlights
The vertebrate lens is composed by an anterior layer of cuboidal epithelial cells and differentiated fiber cells that comprise the bulk of the tissue [1]
FGF-2 Induces Mip Expression in Rat Lens Explants—Previous studies have shown that FGF-1 and FGF-2 promote lens epithelial cell proliferation and differentiation in lens explant cultures [19, 20]
Real time PCR results demonstrated that at the highest dose (100 ng/ml), FGF-2 is significantly more potent in inducing Mip transcription after 3 to 4 days in culture. These results demonstrate that the concentration of FGF-2 is critical both for the morphological changes and Mip expression associated with lens fiber cell differentiation
Summary
The vertebrate lens is composed by an anterior layer of cuboidal epithelial cells and differentiated fiber cells that comprise the bulk of the tissue [1]. MIP may have structural roles in the lens fibers, functioning as a cell to cell adhesion molecule [6, 7], playing a role in gap junction formation [8, 9] and in organizing ␥-crystallins [10] In this way, MIP may play an important role in maintaining lens transparency by reducing the inter-fiber space and is required for the normal focusing properties of the lens [11]. Expression of the Mip gene in the lens is tightly regulated temporally and spatially during embryogenesis, signaling cascades involved in this process remain unidentified. Growth factors such as FGFs, insulin-like growth factor-1, platelet-derived growth factor, epidermal growth factor, and insulin are shown to promote proliferation of lens epithelial cells and differentiation into fiber cells in rats and chicken (19 –24). Experiments using dominant-negative FGF receptors provide insights into the role of FGFs in lens cell survival [29, 33, 34]
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