The overall objective of this research is to understand the molecular basis of cell-cell interactions that regulate retinal neurogenesis during development and regeneration. The accumulated evidence from many laboratories working both in vivo and in vitro and with a number of different vertebrate species suggests that the developmental potential of a progenitor cell, i.e. its ability to produce specific retinal cell types, is progressively altered during retinal development. This proposal concentrates on a selected subset of the molecular interactions that are likely to be involved in determination of cell fate in retinal progenitor cells: cell surface signaling molecules -- the cadherin family of adhesion molecules and the Notch-Delta signaling pathway and the transcriptional regulators it modulates, and the paired-like homeodomain proteins that have been implicated in the control of proliferation and determination of selected progenitor classes. The investigator proposes to examine the expression and function of R-cadherin, identify which cadherin(s) are expressed in photoreceptors, then block their function in the developing retina with antibodies and antisense oligonucleotides and examine specific effects on lamination and cell differentiation. Retinal progenitor cells will be surveyed for subpopulations that express selected combinations of paired-like molecules in the Notch pathway including their downstream targets, neural determination genes, and cadherins. The investigator will then test the hypothesis that combinatorial patterns of expression of regulatory genes reflect developmental potential, from pluripotent stem cells to committed progenitors. This """"""""retinopoiesis"""""""" model will also be tested in a retinal regeneration assay developed in goldfish and now proposed to extend to zebrafish. The studies outlined here, designed to uncover mechanisms involved in retinal cell determination and differentiation and the regenerative replacement of cells in the retina, may provide insights into replacement therapies for damaged human retinal tissue.
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