The development of any tissue requires a temporally regulated series of events, including the orderly production of different cell types. The development of the vertebrate retina is no exception, with a conserved order of production of neurons and glia. The mechanism(s) used to drive this order is unknown. The retinal progenitor cells that produce this order are multipotent throughout development, but have not been shown to be totipotent throughout development. They thus might differ in the types of cells that they can make at any one time. Current data support such a model, wherein retinal progenitor cells undergo temporally regulated changes in their competence to make the distinctive types of neurons over time. It is of interest to define the gene expression history of retinal progenitor cells, and correlate this with the types of progeny cells that they produce. In addition, it is likely that different types of progenitor cells are defined by their transcription factor networks. It is thus also of interest to learn about the functions of the transcription factors that define these temporal states. Therapies that enable stem cells to replace dying or diseased cells will require the instruction of stem cells for production of the proper cell types, e.g. rod and cone photoreceptor cells. In addition, when development does not proceed normally, due to genetic or environmental influences, blindness is a frequent outcome. An understanding of the mechanisms that direct cell fates will greatly enable the instruction of stem cells, and/or other types of therapies that can address developmental abnormalities.

Public Health Relevance

Therapies that enable stem cells to replace dying or diseased cells will require the instruction of stem cells for production of the proper cell types, e.g. rod and cone photoreceptor cells. In addition, when development does not proceed normally, due to genetic or environmental influences, blindness is a frequent outcome. An understanding of the mechanisms that direct cell fates will greatly enable the instruction of stem cells, and/or other types of therapies that can address developmental abnormalities.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY008064-22
Application #
8197362
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Greenwell, Thomas
Project Start
1989-04-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
22
Fiscal Year
2012
Total Cost
$401,063
Indirect Cost
$161,063
Name
Harvard University
Department
Genetics
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Hafler, Brian P; Surzenko, Natalia; Beier, Kevin T et al. (2012) Transcription factor Olig2 defines subpopulations of retinal progenitor cells biased toward specific cell fates. Proc Natl Acad Sci U S A 109:7882-7
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
Beier, Kevin T; Samson, Maria Elena S; Matsuda, Takahiko et al. (2011) Conditional expression of the TVA receptor allows clonal analysis of descendents from Cre-expressing progenitor cells. Dev Biol 353:309-20
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
Trimarchi, Jeffrey M; Stadler, Michael B; Cepko, Constance L (2008) Individual retinal progenitor cells display extensive heterogeneity of gene expression. PLoS One 3:e1588
Roesch, Karin; Jadhav, Ashutosh P; Trimarchi, Jeffrey M et al. (2008) The transcriptome of retinal Muller glial cells. J Comp Neurol 509:225-38
Trimarchi, Jeffrey M; Stadler, Michael B; Roska, Botond et al. (2007) Molecular heterogeneity of developing retinal ganglion and amacrine cells revealed through single cell gene expression profiling. J Comp Neurol 502:1047-65
Matsuda, Takahiko; Cepko, Constance L (2007) Controlled expression of transgenes introduced by in vivo electroporation. Proc Natl Acad Sci U S A 104:1027-32
Rowan, Sheldon; Cepko, Constance L (2005) A POU factor binding site upstream of the Chx10 homeobox gene is required for Chx10 expression in subsets of retinal progenitor cells and bipolar cells. Dev Biol 281:240-55
Kim, Jong-So; Coon, Steven L; Blackshaw, Seth et al. (2005) Methionine adenosyltransferase:adrenergic-cAMP mechanism regulates a daily rhythm in pineal expression. J Biol Chem 280:677-84

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