Fibroblast growth factors (FGFs) and bone morphogenetic proteins (BMPs) play key roles in the development of the mammalian lens. However, the functions of individual BMP and FGF receptors and the mechanisms by which they regulate lens development are not known. Using conditional gene targeting, we show that FGF signaling provides important survival signals for lens epithelial and fiber cells and that different FGF receptors cooperate to promote fiber cell differentiation. BMP receptor-la (Alk3) is also required in fiber cell differentiation. A second type-1 BMP receptor, Alk2, regulates the rate of proliferation of lens epithelial cells. Deletion of Alk2 and Alk3 or Alk3 and a third BMP receptor, Alk6, causes failure of lens induction. None of these phenotypes occur when the BMP mediator Smad4 is deleted, suggesting that Smad-independent signaling is common in lens development. We propose to determine the mechanisms responsible for these phenotypes using immunochemical methods, microarray analysis, and by deleting other genes in the pathways activated by these receptors. Our studies also reveal that the retinoblastoma protein (pRb), a ubiquitous cell cycle regulatory protein, is unexpectedly hyperphosphorylated in terminally differentiated lens fiber cells. Using genetic models with defective fiber cell differentiation, we will determine how covalent modifications of pRb correlate with lens fiber cell differentiation. Exposure of lens cells to TGFbeta leads to pathological fibrosis, as often occurs following cataract surgery. Conditional deletion of TGFbetaRII shows that TGFbeta signaling is not the only cause of lens fibrosis. We will use gene targeting to test the interactions of TGFbeta with other factors in lens fibrosis. We also found that the PPARgamma agonist, troglitazone, blocks lens epithelial fibrosis. We will determine how PPARgamma signaling blocks fibrosis, including the possibility it interacts with the TGFbeta signaling system. The results of these studies are expected to provide important insight into the mechanisms of congenital cataracts and the fibrosis that commonly follows cataract surgery.
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