The central nervous system (CNS) has many neuronal cell types, and within a given brain region, these different types of neurons are present in precise ratios. Such regular ratios of neurons are characteristic of all brain regions and are fundamental to the proper functioning of the nervous system. However, virtually nothing is known of the mechanisms that regulate the production of the various types of neurons during the development of the CNS. Several lines of evidence indicate that this process is in some way controlled by the microenvironment of the developing CNS. The experiments outlined in this proposal will test several specific predictions of a model of central neurogenesis in which age-dependent changes in the retinal microenvironment determine the types of neurons that are produced at any given time. The experiments can be divided into two parts: 1. What factors regulate the proliferation of the germinal neuroepithelial cells during retinal histogenesis? 2. What are the cellular and molecular mechanisms involved in the generation of particular types of neurons/glia from the multipotent progenitor? An understanding of the factors that regulate CNS neuronal proliferation will undoubtedly prove invaluable in future attempts at reconstruction and regeneration of the damaged CNS as well as providing insight into the mechanisms of teratological agents that disrupt the normal development of the nervous system and neoplastic transformation of germinal neuroepithelial cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS028308-07
Application #
2266859
Study Section
Visual Sciences C Study Section (VISC)
Project Start
1989-09-01
Project End
1996-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
7
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Washington
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Liu, Hong; Etter, Paige; Hayes, Susan et al. (2008) NeuroD1 regulates expression of thyroid hormone receptor 2 and cone opsins in the developing mouse retina. J Neurosci 28:749-56
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Nelson, Branden R; Gumuscu, Burak; Hartman, Byron H et al. (2006) Notch activity is downregulated just prior to retinal ganglion cell differentiation. Dev Neurosci 28:128-41
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Lamba, Deepak A; Karl, Mike O; Ware, Carol B et al. (2006) Efficient generation of retinal progenitor cells from human embryonic stem cells. Proc Natl Acad Sci U S A 103:12769-74
Roberts, Melanie R; Srinivas, Maya; Forrest, Douglas et al. (2006) Making the gradient: thyroid hormone regulates cone opsin expression in the developing mouse retina. Proc Natl Acad Sci U S A 103:6218-23
McCabe, Kathryn Leigh; McGuire, Chris; Reh, Thomas A (2006) Pea3 expression is regulated by FGF signaling in developing retina. Dev Dyn 235:327-35
Roberts, Melanie R; Hendrickson, Anita; McGuire, Christopher R et al. (2005) Retinoid X receptor (gamma) is necessary to establish the S-opsin gradient in cone photoreceptors of the developing mouse retina. Invest Ophthalmol Vis Sci 46:2897-904
Elias, Maria C; Tozer, Kathleen R; Silber, John R et al. (2005) TWIST is expressed in human gliomas and promotes invasion. Neoplasia 7:824-37

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