The vertebrate eye and retina have provided important models to identify fundamental processes of developmental such as induction, morphogenesis, patterning and cell fate specification. While a considerate amount of information describing the early events of eye development has been uncovered, many processes of later stages of differentiation and maturation are less well understood. For example, the well characterized, laminar organization of the vertebrate retina is complimented by the non-random or mosaic arrangement of neurons within each of the layers. Though the necessity of the mosaic arrangement is intuitive: gaps in the distribution of neurons or clustering of cells would result in under representation or oversampling of portions of the visual field, little is known of the genetic mechanisms regulating the mosaic patterning. Over the next five years, we propose a novel genetic screen of post-embryonic stage larvae and adult progeny of ENU-mutagenized zebrafish to uncover novel recessive and dominant mutations affecting the visual system. A systematic screen for late onset mutations should provide much needed models of inherited diseases in humans such as retinitis pigmentosa, congenital cataracts and glaucoma.
Three specific aims are proposed:
SPECIFIC AIM I : Recover novel, recessive mutations that specifically affect the specification and mosaic patterning of photoreceptor cells through an in situ immunohistochemical screen of the rod mosaic in free swimming, 5 day old larvae.
SPECIFIC AIM II : Identify genes essential to the development and maintenance of the anterior segment, through a morphological screen for defects in the lens, cornea and pupil of the larval eye.
SPECIFIC AIM III : Identify mutations resulting in photoreceptor cell dystrophies as models of human retinal disease through the histological and immunofluorescent analysis of retinas of adult zebrafish. The initial mutagenesis procedure and subsequent breeding strategy incorporated a mapping panel into the mutagenized lines to facilitate more efficient mapping and the subsequent cloning of the mutated genes. Descriptions and images of the mutant phenotypes will be available at the PI's website and the Zebrafish Information Network and distribution will be handled through the Zebrafish International Resource Center.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY017753-04
Application #
7645694
Study Section
Special Emphasis Panel (ZRG1-BDA-F (50))
Program Officer
Chin, Hemin R
Project Start
2006-08-01
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
4
Fiscal Year
2009
Total Cost
$317,060
Indirect Cost
Name
Florida State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
790877419
City
Tallahassee
State
FL
Country
United States
Zip Code
32306
Sotolongo-Lopez, Mailin; Alvarez-Delfin, Karen; Saade, Carole J et al. (2016) Genetic Dissection of Dual Roles for the Transcription Factor six7 in Photoreceptor Development and Patterning in Zebrafish. PLoS Genet 12:e1005968
Taylor, Scott M; Alvarez-Delfin, Karen; Saade, Carole J et al. (2015) The bHLH Transcription Factor NeuroD Governs Photoreceptor Genesis and Regeneration Through Delta-Notch Signaling. Invest Ophthalmol Vis Sci 56:7496-515
Yoshimatsu, Takeshi; Williams, Philip R; D'Orazi, Florence D et al. (2014) Transmission from the dominant input shapes the stereotypic ratio of photoreceptor inputs onto horizontal cells. Nat Commun 5:3699
Saade, Carole J; Alvarez-Delfin, Karen; Fadool, James M (2013) Rod photoreceptors protect from cone degeneration-induced retinal remodeling and restore visual responses in zebrafish. J Neurosci 33:1804-14
Brockerhoff, Susan E; Fadool, James M (2011) Genetics of photoreceptor degeneration and regeneration in zebrafish. Cell Mol Life Sci 68:651-9
Morris, Ann C; Forbes-Osborne, Marie A; Pillai, Lakshmi S et al. (2011) Microarray analysis of XOPS-mCFP zebrafish retina identifies genes associated with rod photoreceptor degeneration and regeneration. Invest Ophthalmol Vis Sci 52:2255-66
Alvarez-Delfin, Karen; Morris, Ann C; Snelson, Corey D et al. (2009) Tbx2b is required for ultraviolet photoreceptor cell specification during zebrafish retinal development. Proc Natl Acad Sci U S A 106:2023-8
Morris, Ann C; Scholz, Tamera; Fadool, James M (2008) Rod progenitor cells in the mature zebrafish retina. Adv Exp Med Biol 613:361-8
Fadool, James M; Dowling, John E (2008) Zebrafish: a model system for the study of eye genetics. Prog Retin Eye Res 27:89-110
Morris, Ann C; Scholz, Tamera L; Brockerhoff, Susan E et al. (2008) Genetic dissection reveals two separate pathways for rod and cone regeneration in the teleost retina. Dev Neurobiol 68:605-19

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