Retinal Epithelial Polarity and Cellular Patterning

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DESCRIPTION (provided by applicant): Retinal engineering is likely to be the ultimate cure for blinding disorders caused by degeneration of retinal cells. A prerequisite for retinal engineering is understanding the mechanisms of cellular pattern formation in the vertebrate retina. Our long-term research interest is to define these mechanisms. Recent studies suggest that the polarity of the retinal epithelia plays an essential role in neural retinal pattern formation; but the mechanisms involved are largely unknown. We have shown that three zebrafish polarity genes (nok, Pard3, and zLinT) are required to establish the cellular architecture of the mature retina. These proteins all contain well-established protein-protein interaction domains. Our data suggest that zLin7 likely interacts with Nok and that Nok is required for the interactions between the neural retina and the juxtaposed retinal pigmented epithelium (RPE). Our central hypothesis is that Nok, Pard3, and zLin7 associate with other proteins in a developmentally regulated fashion to collectively establish and/or maintain the proper polarity of retinal epithelia and consequently ensure accurate interactions between the neural retina and RPE. These interactions likely enable the proper distribution of cell migration cues required for retinal pattern formation. The major aims of the research to be pursued in this project include: 1) Determine to what extent Nok's function in controlling cellular pattern formation in the neural retina requires Nok's activity in the RPE by making and analyzing transgenic embryos that display mosaic Nok expressions in the eye; 2) Determine whether Nok physically interacts with one or more isoforms of zLin7's and what protein domains are involved in the interaction; 3) Identify and characterize the proteins that interact with Nok, Pard3, and zLin7 complexes during retinal development by using affinity purification, yeast two-hybrid, and candidate genes approaches.