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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Paulus, Jeremiah D; Link, Brian A (2014) Loss of optineurin in vivo results in elevated cell death and alters axonal trafficking dynamics. PLoS One 9:e109922
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
Willardsen, Minde I; Link, Brian A (2011) Cell biological regulation of division fate in vertebrate neuroepithelial cells. Dev Dyn 240:1865-79
Clark, Brian S; Winter, Mark; Cohen, Andrew R et al. (2011) Generation of Rab-based transgenic lines for in vivo studies of endosome biology in zebrafish. Dev Dyn 240:2452-65
Bachmann-Gagescu, Ruxandra; Phelps, Ian G; Stearns, George et al. (2011) The ciliopathy gene cc2d2a controls zebrafish photoreceptor outer segment development through a role in Rab8-dependent vesicle trafficking. Hum Mol Genet 20:4041-55
Insinna, Christine; Baye, Lisa M; Amsterdam, Adam et al. (2010) Analysis of a zebrafish dync1h1 mutant reveals multiple functions for cytoplasmic dynein 1 during retinal photoreceptor development. Neural Dev 5:12
Choi, Jung-Hwan; Law, Mei-Yee; Chien, Chi-Bin et al. (2010) In vivo development of dendritic orientation in wild-type and mislocalized retinal ganglion cells. Neural Dev 5:29
Hava, David; Forster, Ulrike; Matsuda, Miho et al. (2009) Apical membrane maturation and cellular rosette formation during morphogenesis of the zebrafish lateral line. J Cell Sci 122:687-95
Baye, Lisa M; Link, Brian A (2008) Nuclear migration during retinal development. Brain Res 1192:29-36

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