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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY004853-27
Application #
7848158
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Araj, Houmam H
Project Start
1983-12-01
Project End
2011-08-31
Budget Start
2010-07-01
Budget End
2011-08-31
Support Year
27
Fiscal Year
2010
Total Cost
$555,264
Indirect Cost
Name
Washington University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Oltean, Alina; Huang, Jie; Beebe, David C et al. (2016) Tissue growth constrained by extracellular matrix drives invagination during optic cup morphogenesis. Biomech Model Mechanobiol 15:1405-1421
Huang, Jie; Liu, Ying; Filas, Benjamen et al. (2015) Negative and positive auto-regulation of BMP expression in early eye development. Dev Biol 407:256-64
Huang, Jie; Liu, Ying; Oltean, Alina et al. (2015) Bmp4 from the optic vesicle specifies murine retina formation. Dev Biol 402:119-26
Chen, Ziyan; Huang, Jie; Liu, Ying et al. (2014) FGF signaling activates a Sox9-Sox10 pathway for the formation and branching morphogenesis of mouse ocular glands. Development 141:2691-701
Xie, Qing; Yang, Ying; Huang, Jie et al. (2013) Pax6 interactions with chromatin and identification of its novel direct target genes in lens and forebrain. PLoS One 8:e54507
Wolf, Louise; Harrison, Wilbur; Huang, Jie et al. (2013) Histone posttranslational modifications and cell fate determination: lens induction requires the lysine acetyltransferases CBP and p300. Nucleic Acids Res 41:10199-214
Li, Qi; Yan, Hong; Ding, Tian-Bing et al. (2013) Oxidative responses induced by pharmacologic vitreolysis and/or long-term hyperoxia treatment in rat lenses. Curr Eye Res 38:639-48
Almony, Arghavan; Holekamp, Nancy M; Bai, Fang et al. (2012) Small-gauge vitrectomy does not protect against nuclear sclerotic cataract. Retina 32:499-505
Garcia, Claudia M; Huang, Jie; Madakashira, Bhavani P et al. (2011) The function of FGF signaling in the lens placode. Dev Biol 351:176-85
Wiley, Luke A; Rajagopal, Ramya; Dattilo, Lisa K et al. (2011) The tumor suppressor gene Trp53 protects the mouse lens against posterior subcapsular cataracts and the BMP receptor Acvr1 acts as a tumor suppressor in the lens. Dis Model Mech 4:484-95

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