Integrated signaling is critical both during retinal development and in maintenance of mature neurons. Using zebrafish, we have developed a series of transgenic and mutant tools to probe the regulation and relationships between two pathways important for normal retinal development, Notch and Hippo-Yap/Taz. We will investigate how individual cellular processes, particularly endocytosis and endomembrane trafficking, shape these pathways. Attention will be placed on components of each pathway as well a Crumbs, which has been shown to tune both Notch and Hippo-Yap/Taz. In addition to assessing the nuances of pathway regulation, we will also test the precise function of each signaling module on retinogenesis. Last, we address the function of Crumbs mediated Hippo-Yap/Taz-Tead signaling in photoreceptor homeostasis. The proposed experiments address basic cellular questions on the nature of Notch and Hippo/Yap signaling. This research, therefore, has implications for improving stem cell manipulation and a better defining targets for slowing or preventing photoreceptor degenerations. !

Public Health Relevance

During both retinal development and in the maintenance of mature retinal neurons such as photoreceptor cells, various signaling pathways must be precisely regulated. In this proposal we describe studies primarily in zebrafish to understand the relationships between two signaling modules implicated both during development and in tissue homeostasis.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (BVS)
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Greenwell, Thomas
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Medical College of Wisconsin
Anatomy/Cell Biology
Schools of Medicine
United States
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Lewis, Tylor R; Kundinger, Sean R; Link, Brian A et al. (2018) Kif17 phosphorylation regulates photoreceptor outer segment turnover. BMC Cell Biol 19:25
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Porazinski, Sean; Wang, Huijia; Asaoka, Yoichi et al. (2015) YAP is essential for tissue tension to ensure vertebrate 3D body shape. Nature 521:217-221
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Miesfeld, Joel B; Link, Brian A (2014) Establishment of transgenic lines to monitor and manipulate Yap/Taz-Tead activity in zebrafish reveals both evolutionarily conserved and divergent functions of the Hippo pathway. Mech Dev 133:177-88
Clark, Brian S; Cui, Shuang; Miesfeld, Joel B et al. (2012) Loss of Llgl1 in retinal neuroepithelia reveals links between apical domain size, Notch activity and neurogenesis. Development 139:1599-610

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