The long-range objective of the proposed research is to determine the cellular and molecular events that lead to the differentiation of specific cell types in the vertebrate retina. We continue our emphasis on the roles of extracellular factors in regulating photoreceptor diversity and differentiation, as the work of the current funding period has demonstrated the significance of these factors not only for photoreceptor differentiation, but also for photoreceptor fate and for photoreceptor maintenance. Our work has provided in vivo evidence that the extracellular factor retinoic acid (RA) influences rod vs. cone neurogenesis when supplied to late retinal progenitors. In addition, RA selectively regulates the differentiation of specific photoreceptor populations when supplied later in retinal development. These regulatory functions are distinct from those of the extracellular factor Hedgehog (Hh), which is required for differentiation of all photoreceptor types, and which is required throughout the lifespan for cone photoreceptor maintenance. In the proposed award period, we will build on these studies through the evaluation of specific extracellular factors on photoreceptor fate and differentiation, examining cell-selective effects on networks of genes involved in rod and cone determination, differentiation, and in photoreceptor pathology. We apply a combination of genetic, molecular, pharmacological, histological, computational, and bioinformatics tools to the zebrafish model. We will test the following hypotheses:1) that RA and Notch signaling control rod vs. cone fate;2) that the microenvironmental factors RA and Hh selectively manipulate cell-specific gene networks during photoreceptor differentiation;and 3) that limiting quantities of Hh signaling throughout the lifespan will engage a photoreceptor damage response.
Visual function requires the collaborative activities of a diverse, but properly arranged collection of specialized cells. Our goal is to understand the mechanisms that underlie the development and survival of photoreceptor cells, which are required for visual function, and which are lost in many visual degenerative diseases. Our findings will have applications for the development of photoreceptor replacement strategies and photoreceptor survival therapies, as well as for the prevention and treatment of developmental abnormalities of the retina.
|Mitchell, Diana M; Stevens, Craig B; Frey, Ruth A et al. (2015) Retinoic Acid Signaling Regulates Differential Expression of the Tandemly-Duplicated Long Wavelength-Sensitive Cone Opsin Genes in Zebrafish. PLoS Genet 11:e1005483|
|Dhakal, Susov; Stevens, Craig B; Sebbagh, Meyrav et al. (2015) Abnormal retinal development in Cloche mutant zebrafish. Dev Dyn 244:1439-55|
|Stenkamp, Deborah L (2015) Development of the Vertebrate Eye and Retina. Prog Mol Biol Transl Sci 134:397-414|
|Sherpa, Tshering; Lankford, Tyler; McGinn, Tim E et al. (2014) Retinal regeneration is facilitated by the presence of surviving neurons. Dev Neurobiol 74:851-76|
|Kashyap, Bhavani; Pegorsch, Laurel; Frey, Ruth A et al. (2014) Eye-specific gene expression following embryonic ethanol exposure in zebrafish: roles for heat shock factor 1. Reprod Toxicol 43:111-24|
|Stenkamp, Deborah L (2011) The rod photoreceptor lineage of teleost fish. Prog Retin Eye Res 30:395-404|
|Kashyap, Bhavani; Frey, Ruth A; Stenkamp, Deborah L (2011) Ethanol-induced microphthalmia is not mediated by changes in retinoic acid or sonic hedgehog signaling during retinal neurogenesis. Alcohol Clin Exp Res 35:1644-61|
|Sherpa, Tshering; Hunter, Samuel S; Frey, Ruth A et al. (2011) Retinal proliferation response in the buphthalmic zebrafish, bugeye. Exp Eye Res 93:424-36|
|Stevens, Craig B; Cameron, David A; Stenkamp, Deborah L (2011) Plasticity of photoreceptor-generating retinal progenitors revealed by prolonged retinoic acid exposure. BMC Dev Biol 11:51|
|Nelson, Steve M; Mahmoud, Tarek; Beaux 2nd, Miles et al. (2010) Toxic and teratogenic silica nanowires in developing vertebrate embryos. Nanomedicine 6:93-102|
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