The overall goal of this proposal is to understand how the vertebrate retina forms organized layers. We are proposing a novel integrative approach in zebrafish to address what are the essential molecules, critical cell types, and important cellular behaviors that facilitate proper cell fate and positioning within the retina. Previously we have isolated mutations in zebrafish which specifically disrupt retinal lamination. We have also taken advantage of the transparency of zebrafish embryos to establish techniques which allow us to track individual cells in vivo as the retina develops. This grant proposes experiments that combine these two experimental tacts: mutation analysis and cell behavior studies. The focus of this proposal is on the period from when a proliferating retinoblast enters its last cell cycle to when it completes migration away from the verticular zone. This encompasses the time when cells become specified to particular cell types to when laminar position is established. In accordance with our goal, the early lamination mutations which affect this developmental stage (disarrayed, bewildered, perplexed, and young) and the cellular behaviors that occur during this transition (interkinetic nuclear migration, final cell division orientation, and post-mitotic cell migration) will be systematically studied. In addition, we will use molecular genetics to identify the mutated genes. Because the genes and cells that are utilized during development invariably have maintenance roles within the adult, and therefore underlie pathogenic states, our studies can provide insights into mechanisms that lead to retinal diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY014167-04
Application #
7025685
Study Section
Special Emphasis Panel (ZRG1-VISC (01))
Program Officer
Hunter, Chyren
Project Start
2003-03-01
Project End
2008-02-28
Budget Start
2006-03-01
Budget End
2008-02-28
Support Year
4
Fiscal Year
2006
Total Cost
$304,435
Indirect Cost
Name
Medical College of Wisconsin
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Lewis, Tylor R; Kundinger, Sean R; Link, Brian A et al. (2018) Kif17 phosphorylation regulates photoreceptor outer segment turnover. BMC Cell Biol 19:25
Lewis, Tylor R; Zareba, Mariusz; Link, Brian A et al. (2018) Cone myoid elongation involves unidirectional microtubule movement mediated by dynein-1. Mol Biol Cell 29:180-190
Prokop, Jeremy W; Yeo, Nan Cher; Ottmann, Christian et al. (2018) Characterization of Coding/Noncoding Variants for SHROOM3 in Patients with CKD. J Am Soc Nephrol 29:1525-1535
Lewis, Tylor R; Kundinger, Sean R; Pavlovich, Amira L et al. (2017) Cos2/Kif7 and Osm-3/Kif17 regulate onset of outer segment development in zebrafish photoreceptors through distinct mechanisms. Dev Biol 425:176-190
Miesfeld, Joel B; Gestri, Gaia; Clark, Brian S et al. (2015) Yap and Taz regulate retinal pigment epithelial cell fate. Development 142:3021-32
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
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
Tang, Yujie; Gholamin, Sharareh; Schubert, Simone et al. (2014) Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nat Med 20:732-40
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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