This proposal investigates the underlying causes of human ocular diseases using mouse models. We focus on the Notch signaling pathway, which is critically required in multiple mammalian tissues. In particular, Notch signaling regulates proliferation, apoptosis, cell shape changes, differentiation and stem cell maintenance. Experiments in this proposal will 1) elucidate the epistatic relationship between Notch signaling and Math5 during retinal ganglion cell (RGC) neurogenesis 2) explore the multiple retinal neuron phenotypes of Rbpj, and 3) define the requirements of the Notch ligand Deltalike1 during retinal neurogenesis. Because Notch signaling is widely employed during development, mouse mutations in most Notch pathway genes have already been created. Using targeted deletion mice (wholly mutant and conditional alleles), we propose to understand the requirements for canonical Notch signaling during retinal ganglion cell and cone and rod photoreceptor formation. Some studies will employ conditional (cre-lox) mouse strains, histology, immunohistochemistry, in situ hybridization, mouse embryology and PCR genotyping. Others will test regulatory relationships in vitro using a human retinoblast cell line. These studies will contribute new information to the processes of growth, morphogenesis and differentiation, which are fundamental to all metazoan development. This work will yield a better understanding of cone-rod dystrophies, optic nerve aplasia, hypoplasia, as well as contribute to basic mechanisms of retinal cell development with direct relevany to gene- or cell-based retinal therapies. Findings here will also be widely useful to the field of cancer biology, since excess activated Notch1 or Hes1 expression occurs in a variety of human tumors.

Public Health Relevance

The goal of this study is to understand the underlying molecular mechanisms of how mammalian retinal neurons forms, using mouse models. We propose to do this by investigating which aspects of retinal formation require the Notch cell-to-cell signaling pathway, and how it regulates the Math5 bHLH transcription factor. In other parts of the body, Notch signaling controls cell shape changes, growth, and death. For these reasons, mutations in the Notch pathway can cause cancer. A thorough understanding of how, when and where Notch acts in the retina has only been addressed superficially. These studies will provide deeper understanding, at the single cell level, of how the retina develops and contribute to the better design of disease therapies for diseases such as Leber's congeital amaurosis, cone-rod dystrophy, color blindness, optic nerve aplasia/hyplasia and glaucoma.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013612-11
Application #
8113428
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Neuhold, Lisa
Project Start
2001-08-01
Project End
2011-12-31
Budget Start
2011-08-01
Budget End
2011-12-31
Support Year
11
Fiscal Year
2011
Total Cost
$96,778
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Baker, Nicholas E; Brown, Nadean L (2018) All in the family: proneural bHLH genes and neuronal diversity. Development 145:
Miesfeld, Joel B; Moon, Myung-Soon; Riesenberg, Amy N et al. (2018) Rbpj direct regulation of Atoh7 transcription in the embryonic mouse retina. Sci Rep 8:10195
Riesenberg, Amy N; Conley, Kevin W; Le, Tien T et al. (2018) Separate and coincident expression of Hes1 and Hes5 in the developing mouse eye. Dev Dyn 247:212-221
Kowalchuk, Angelica M; Maurer, Kate A; Shoja-Taheri, Farnaz et al. (2018) Requirements for Neurogenin2 during mouse postnatal retinal neurogenesis. Dev Biol 442:220-235
Maurer, Kate A; Kowalchuk, Angelica; Shoja-Taheri, Farnaz et al. (2018) Integral bHLH factor regulation of cell cycle exit and RGC differentiation. Dev Dyn 247:965-975
Miesfeld, Joel B; Glaser, Tom; Brown, Nadean L (2018) The dynamics of native Atoh7 protein expression during mouse retinal histogenesis, revealed with a new antibody. Gene Expr Patterns 27:114-121
Zhang, Qi; Zagozewski, Jamie; Cheng, Shaohong et al. (2017) Regulation of Brn3b by DLX1 and DLX2 is required for retinal ganglion cell differentiation in the vertebrate retina. Development 144:1698-1711
Riesenberg, Amy N; Brown, Nadean L (2016) Cell autonomous and nonautonomous requirements for Delltalike1 during early mouse retinal neurogenesis. Dev Dyn 245:631-40
Maurer, Kate A; Riesenberg, Amy N; Brown, Nadean L (2014) Notch signaling differentially regulates Atoh7 and Neurog2 in the distal mouse retina. Development 141:3243-54
Hufnagel, Robert B; Riesenberg, Amy N; Quinn, Malgorzata et al. (2013) Heterochronic misexpression of Ascl1 in the Atoh7 retinal cell lineage blocks cell cycle exit. Mol Cell Neurosci 54:108-20

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