This proposal investigates the underlying causes of human ocular diseases using mouse models, focusing on both the Notch signaling pathway, which is broadly required during development, and two classes of bHLH transcription factors (Atoh7/Neurog2 or Hes genes). The activities of both types of factors are regulated by Notch signaling, in particular developmental contexts. The Notch pathway is also responsible for regulating cell proliferation, morphogenesis, differentiation, apoptosis and stem cell maintenance. Dominant mutations in the human Notch pathway genes JAG1 and NOTCH2 cause Alagille syndrome, in which some patients exhibit eye deformities. This proposal will use complex conditional (cre-lox) mouse strains, including double and triple mutants, histology, immunohistochemistry, confocal microscopy, in situ hybridization, mouse embryology, flow cytometry, NEXTgen sequencing, bioinformatics, ChIP, qPCR, and PCR technologies to address basic, mechanistic questions about retinal neuron formation. We will address two important questions, namely 1) Which genes regulate optic nerve head development and maintain the boundary between the retina and optic stalk? 2) What controls retinal progenitor cell differentiation into either a retinal ganglion cell or a cone photoreceptor neuron?

Public Health Relevance

This research will provide fundamental understanding of the process of optic fissure formation and closure, which ultimately inform the pathogenesis and/or treatment of congenital diseases like coloboma, microphthalmia, optic nerve hypoplasia, Leber's congenital amaurosis, and pediatric and adult onset glaucoma. This research project addresses several objectives recommended by the Retinal Diseases Panel ( which are to 'Identify and characterize genes responsible for optic nerve disease' and 'Develop transgenic and other animal models of optic nerve disease'. In a broader context, our experiments will also contribute new information about Notch signaling regulation of multiple bHLH transcription factors.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Greenwell, Thomas
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University of California Davis
Anatomy/Cell Biology
Schools of Medicine
United States
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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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