Regulation of lens development requires the coordinated activities of a number of growth factor signaling pathways, cell-cell and cell-matrix adhesion complexes, and cell cycle regulators. An important question is how all these different pathways are spatially and temporally coordinated so as to ensure proper lens formation. PDZ (PSD95/DLG/ZO-1) proteins are proteins that have the potential capacity to link all of these molecular pathways. Through their capacity to act as scaffolds, they assemble large protein complexes that, depending on the constituent molecules assembled, signal towards different cellular fates. In Drosophila, the tumor suppressor genes Discs Large (dig) and Scribble (scrib), which encode two PDZ proteins, are essential for establishing and maintaining normal epithelial cell structure, polarity and proliferation. Our recent transgenic mouse studies using of the E6 oncoprotein from human papillomavirus as a dominant inhibitor of PDZ proteins, suggests a heretofore unrecognized role for PDZ proteins such as Dlg-1 and Scrib in many stages of lens development. We also have shown that a hypomorphic allele of Dlg-1 gives rise to cataractous abnormalities in the mouse lens during embryogenesis. In this application, we propose to use a combination of genetic and molecular analyses on mouse mutants in Dlg-1, Scrib, and other interacting genes to (1) determine the requirements for Dlg-1 and/or Scrib in lens development, (2) determine if, and the mechanisms through which, Dlg-1 and/or Scrib regulate lens development by modulating cell adhesion protein complexes, and (3) define the pathway through which Dlg-1 and/or Scrib regulate the cell cycle. Loss of cell cycle control, cell architecture and polarity are observed in many cataractous conditions ranging from congenital cataracts to age-related cataracts in adults to secondary cataracts, that occur following cataract surgery. Factors that regulate these fundamental properties of lens cells during embryogenesis have the potential to be relevant to maintaining normal lens structure and transparency throughout the life of the animal. Additionally, defects in PDZ and polarity genes recently have been found to be associated with retinal degenerations in experimental animals and humans. Thus, the knowledge we gain from our novel studies to understand the role of Dlg-1 and Scrib in mouse lens development potentially will have significant impact on our understanding not only of lens development but also cataract, and other ocular diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY009091-19
Application #
8048002
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Araj, Houmam H
Project Start
1992-05-01
Project End
2014-03-31
Budget Start
2011-04-01
Budget End
2014-03-31
Support Year
19
Fiscal Year
2011
Total Cost
$489,750
Indirect Cost
Name
University of Wisconsin Madison
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Lee, SungKyoung; Shatadal, Shalini; Griep, Anne E (2016) Dlg-1 Interacts With and Regulates the Activities of Fibroblast Growth Factor Receptors and EphA2 in the Mouse Lens. Invest Ophthalmol Vis Sci 57:707-18
Lee, SungKyoung; Griep, Anne E (2014) Loss of Dlg-1 in the mouse lens impairs fibroblast growth factor receptor signaling. PLoS One 9:e97470
Yamben, Idella F; Rachel, Rivka A; Shatadal, Shalini et al. (2013) Scrib is required for epithelial cell identity and prevents epithelial to mesenchymal transition in the mouse. Dev Biol 384:41-52
Rivera, Charlene; Simonson, Sara J S; Yamben, Idella F et al. (2013) Requirement for Dlgh-1 in planar cell polarity and skeletogenesis during vertebrate development. PLoS One 8:e54410
Rivera, Charlene; Yamben, Idella F; Shatadal, Shalini et al. (2009) Cell-autonomous requirements for Dlg-1 for lens epithelial cell structure and fiber cell morphogenesis. Dev Dyn 238:2292-308
Griep, Anne E (2006) Cell cycle regulation in the developing lens. Semin Cell Dev Biol 17:686-97
Nguyen, Minh M; Rivera, Charlene; Griep, Anne E (2005) Localization of PDZ domain containing proteins Discs Large-1 and Scribble in the mouse eye. Mol Vis 11:1183-99
Li, Yan; Schlamp, Cassandra L; Poulsen, Gretchen L et al. (2002) p53 regulates apoptotic retinal ganglion cell death induced by N-methyl-D-aspartate. Mol Vis 8:341-50
Stolen, C M; Griep, A E (2000) Disruption of lens fiber cell differentiation and survival at multiple stages by region-specific expression of truncated FGF receptors. Dev Biol 217:205-20
McCaffrey, J; Yamasaki, L; Dyson, N J et al. (1999) Disruption of retinoblastoma protein family function by human papillomavirus type 16 E7 oncoprotein inhibits lens development in part through E2F-1. Mol Cell Biol 19:6458-68

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