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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Visual Sciences C Study Section (VISC)
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Hunter, Chyren
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University of Michigan Ann Arbor
Anatomy/Cell Biology
Schools of Medicine
Ann Arbor
United States
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Sifuentes, Christopher J; Kim, Jung-Woong; Swaroop, Anand et al. (2016) Rapid, Dynamic Activation of Müller Glial Stem Cell Responses in Zebrafish. Invest Ophthalmol Vis Sci 57:5148-5160
Lenkowski, Jenny R; Raymond, Pamela A (2014) Müller glia: Stem cells for generation and regeneration of retinal neurons in teleost fish. Prog Retin Eye Res 40:94-123
Nagashima, Mikiko; Barthel, Linda K; Raymond, Pamela A (2013) A self-renewing division of zebrafish Muller glial cells generates neuronal progenitors that require N-cadherin to regenerate retinal neurons. Development 140:4510-21
Lenkowski, Jenny R; Qin, Zhao; Sifuentes, Christopher J et al. (2013) Retinal regeneration in adult zebrafish requires regulation of TGF? signaling. Glia 61:1687-97
Meyers, Jason R; Hu, Lily; Moses, Ariel et al. (2012) ?-catenin/Wnt signaling controls progenitor fate in the developing and regenerating zebrafish retina. Neural Dev 7:30
Qin, Zhao; Raymond, Pamela A (2012) Microarray-based gene profiling analysis of Müller glia-derived retinal stem cells in light-damaged retinas from adult zebrafish. Methods Mol Biol 884:255-61
Qin, Zhao; Kidd 3rd, Ambrose R; Thomas, Jennifer L et al. (2011) FGF signaling regulates rod photoreceptor cell maintenance and regeneration in zebrafish. Exp Eye Res 93:726-34
Qin, Zhao; Barthel, Linda K; Raymond, Pamela A (2009) Genetic evidence for shared mechanisms of epimorphic regeneration in zebrafish. Proc Natl Acad Sci U S A 106:9310-5
Adler, Ruben; Raymond, Pamela A (2008) Have we achieved a unified model of photoreceptor cell fate specification in vertebrates? Brain Res 1192:134-50
Bernardos, Rebecca L; Barthel, Linda K; Meyers, Jason R et al. (2007) Late-stage neuronal progenitors in the retina are radial Muller glia that function as retinal stem cells. J Neurosci 27:7028-40

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