The long-term goal of this application is an understanding of the mechanisms of early eye development. More specifically, we wish to understand how actin-modulating GTPases influence the coordinated morphogenesis of the lens and retinal epithelium. The Rho family GTPases that are the focus of this application act as molecular switches that regulate signaling within the cell. They function in many different capacities, but have a prominent role in the regulation of actin rearrangement and consequently, the regulation of cell shape, cell migration and the generation of cellular protrusions. They can also influence cell survival. We outline 4 aims to investigate their function in early eye morphogenesis: (1) To determine whether Cdc42 and Rac1 function in a cascade to regulate lens vesicle closure and separation, (2) To determine whether early deletion of Cdc42, Rac1 or RhoA gives a defect in lens pit invagination, (3) To determine whether the optic vesicle has a dominant role in lens pit invagination, and (4) To determine whether the FGF signaling pathway modulates activity of the Rac1, Cdc42 or RhoA pathways. This application has direct significance to human health because the Rho family GTPases are implicated in a variety of human disease including cancer. The involvement of the GTPases in the etiology of cancer is derived from their ability to regulate cell adhesion, cell migration and cell survival. The process of epithelial invagination that we will study is in many ways analogous to the process of invasion that accompanies the development of aggressive cancers. For this reasop, this project may have implications for cancer therapy.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Araj, Houmam H
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Cincinnati Children's Hospital Medical Center
United States
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Maddala, Rupalatha; Nagendran, Tharkika; Lang, Richard A et al. (2015) Rap1 GTPase is required for mouse lens epithelial maintenance and morphogenesis. Dev Biol 406:74-91
Plageman Jr, Timothy F; Lang, Richard A (2012) Generation of an Rx-tTA: TetOp-Cre knock-in mouse line for doxycycline regulated Cre activity in the Rx expression domain. PLoS One 7:e50426
Plageman Jr, Timothy F; Zacharias, Amanda L; Gage, Phillip J et al. (2011) Shroom3 and a Pitx2-N-cadherin pathway function cooperatively to generate asymmetric cell shape changes during gut morphogenesis. Dev Biol 357:227-34
Maddala, Rupalatha; Chauhan, Bharesh K; Walker, Christopher et al. (2011) Rac1 GTPase-deficient mouse lens exhibits defects in shape, suture formation, fiber cell migration and survival. Dev Biol 360:30-43
Chauhan, Bharesh K; Lou, Ming; Zheng, Yi et al. (2011) Balanced Rac1 and RhoA activities regulate cell shape and drive invagination morphogenesis in epithelia. Proc Natl Acad Sci U S A 108:18289-94
Plageman Jr, Timothy F; Chauhan, Bharesh K; Yang, Christine et al. (2011) A Trio-RhoA-Shroom3 pathway is required for apical constriction and epithelial invagination. Development 138:5177-88
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Lin, Shuei-Liong; Li, Bing; Rao, Sujata et al. (2010) Macrophage Wnt7b is critical for kidney repair and regeneration. Proc Natl Acad Sci U S A 107:4194-9
Gordon, Emma J; Rao, Sujata; Pollard, Jeffrey W et al. (2010) Macrophages define dermal lymphatic vessel calibre during development by regulating lymphatic endothelial cell proliferation. Development 137:3899-910
Plageman Jr, Timothy F; Chung, Mei-I; Lou, Ming et al. (2010) Pax6-dependent Shroom3 expression regulates apical constriction during lens placode invagination. Development 137:405-15

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