Photoreceptors are a highly specialized type of neuron with extraordinary properties. Rod photoreceptors are exquisitely sensitive to light due to their precise and unique morphology as well as their highly efficient phototransduction mechanism. They are also the cell type that seems most vulnerable to degeneration in that many genetic and environmental lesions lead to their degeneration. We propose to study the mechanisms of genesis and differentiation of murine rod photoreceptors. Over the last grant period, we characterized the response of retinal cells to two extrinsic cues that negatively and positively regulate rod development, ciliary neurotrophic factor (CNTF) and taurine, respectively. We also characterized a role for the retinal anterior homeobox gene, Rax, in photoreceptor development. We have been developing reagents to probe the molecular consequences of the action of these extrinsic factors and the Rax gene. In addition, we discovered that a number of newly characterized genes are expressed during retinal development in a manner that is highly suggestive of a role in rod development. We pioneered the application of two new techniques, electroporation and RNAi, for rapid manipulation of gene expression levels in the retina in vivo. These new methods, along with the knowledge of many new genes that serve as markers of the rod pathway, will greatly aid in the study of gene function in the development of rod photoreceptors. Our goal is to create a molecular description of the pathway of rod development, including the series of gene expression changes that occur in the pathway, and place the action of the regulators of rod development within this pathway.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY009676-11
Application #
6687595
Study Section
Special Emphasis Panel (ZRG1-VISC (01))
Program Officer
Hunter, Chyren
Project Start
1992-08-01
Project End
2008-06-30
Budget Start
2003-07-15
Budget End
2004-06-30
Support Year
11
Fiscal Year
2003
Total Cost
$378,000
Indirect Cost
Name
Harvard University
Department
Genetics
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Mizeracka, Karolina; DeMaso, Christina R; Cepko, Constance L (2013) Notch1 is required in newly postmitotic cells to inhibit the rod photoreceptor fate. Development 140:3188-97
Emerson, Mark M; Surzenko, Natalia; Goetz, Jillian J et al. (2013) Otx2 and Onecut1 promote the fates of cone photoreceptors and horizontal cells and repress rod photoreceptors. Dev Cell 26:59-72
Mizeracka, Karolina; Trimarchi, Jeffrey M; Stadler, Michael B et al. (2013) Analysis of gene expression in wild-type and Notch1 mutant retinal cells by single cell profiling. Dev Dyn 242:1147-59
Emerson, Mark M; Cepko, Constance L (2011) Identification of a retina-specific Otx2 enhancer element active in immature developing photoreceptors. Dev Biol 360:241-55
Cherry, Timothy J; Wang, Sui; Bormuth, Ingo et al. (2011) NeuroD factors regulate cell fate and neurite stratification in the developing retina. J Neurosci 31:7365-79
Bienvenu, Frédéric; Jirawatnotai, Siwanon; Elias, Joshua E et al. (2010) Transcriptional role of cyclin D1 in development revealed by a genetic-proteomic screen. Nature 463:374-8
Jadhav, Ashutosh P; Roesch, Karin; Cepko, Constance L (2009) Development and neurogenic potential of Muller glial cells in the vertebrate retina. Prog Retin Eye Res 28:249-62
Kim, Douglas S; Matsuda, Takahiko; Cepko, Constance L (2008) A core paired-type and POU homeodomain-containing transcription factor program drives retinal bipolar cell gene expression. J Neurosci 28:7748-64
Damiani, Devid; Alexander, John J; O'Rourke, Jason R et al. (2008) Dicer inactivation leads to progressive functional and structural degeneration of the mouse retina. J Neurosci 28:4878-87
Morrow, Eric M; Chen, C-M Amy; Cepko, Constance L (2008) Temporal order of bipolar cell genesis in the neural retina. Neural Dev 3:2

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