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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Neuhold, Lisa
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University of California Davis
Anatomy/Cell Biology
Schools of Medicine
United States
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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
Macgregor, Stuart; Hewitt, Alex W; Hysi, Pirro G et al. (2010) Genome-wide association identifies ATOH7 as a major gene determining human optic disc size. Hum Mol Genet 19:2716-24
Hufnagel, Robert B; Le, Tien T; Riesenberg, Ashley L et al. (2010) Neurog2 controls the leading edge of neurogenesis in the mammalian retina. Dev Biol 340:490-503
Prasov, Lev; Brown, Nadean L; Glaser, Tom (2010) A critical analysis of Atoh7 (Math5) mRNA splicing in the developing mouse retina. PLoS One 5:e12315
Willardsen, Minde I; Suli, Arminda; Pan, Yi et al. (2009) Temporal regulation of Ath5 gene expression during eye development. Dev Biol 326:471-81
Riesenberg, Amy N; Liu, Zhenyi; Kopan, Raphael et al. (2009) Rbpj cell autonomous regulation of retinal ganglion cell and cone photoreceptor fates in the mouse retina. J Neurosci 29:12865-77
Fuhrmann, Sabine; Riesenberg, Amy N; Mathiesen, Amber M et al. (2009) Characterization of a transient TCF/LEF-responsive progenitor population in the embryonic mouse retina. Invest Ophthalmol Vis Sci 50:432-40
Riesenberg, Amy N; Le, Tien T; Willardsen, Minde I et al. (2009) Pax6 regulation of Math5 during mouse retinal neurogenesis. Genesis 47:175-87
Blackburn, David C; Conley, Kevin W; Plachetzki, David C et al. (2008) Isolation and expression of Pax6 and atonal homologues in the American horseshoe crab, Limulus polyphemus. Dev Dyn 237:2209-19

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