The overall goal of this ongoing research program is to understand the molecular basis of cell-cell interactions that regulate retinal neurogenesis during development and regeneration. The zebrafish (Danio rerio) provides a powerful genetic model in which to define the causal relationships between retinal stem cells and the in vivo microenvironment that support neuronal regeneration and restoration of functional neural circuits in the retina of an adult organism. The concept that retinal neurons and MOiler glia derive from a common progenitor in the developing retina is widely accepted, and it is known that late stage retinal progenitors can generate both rod photoreceptors and MOiler glia. More surprising is the recent discovery that differentiated MOiler glia continue to function as neuronal progenitors, producing rod photoreceptors in the uninjured, adult teleost retina. In response to loss of retinal neurons, MOiler glia in the teleost retina dedifferentiate, reenter the cell cycle and generate multipotent retinal progenitors that generate neurons to repair the damage. A latent and abortive neurogenic capacity of MOiler glia in adult mammalian retinas has been demonstrated, however, almost nothing is known about the molecular regulation that switches MOiler glia from a state of reactive gliosis to neurogenesis. The proposed studies take advantage of zebrafish genetics to discover the cellular and molecular mechanisms that promote the endogenous neurogenic potential of MOiler glia.
The specific aims of the proposed research are to evaluate whether candidate regulatory signaling pathways (Wntlp-catenin, Fgf and Notch) acting upstream of the proneural transcription factor ascl1a are required to activate a neurogenic program in MOiler glia, and to evaluate the hypothesis that epithelial characteristics related to apical-basal polarity regulate the neurogenic response of MOiler glia.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY004318-25
Application #
7860556
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Mariani, Andrew P
Project Start
1983-04-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
25
Fiscal Year
2010
Total Cost
$379,632
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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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