Cones represent only 5% of photoreceptors in humans, but are critical for our daytime vision. AMD, the most prominent cone vision disorder, has a major impact on the elderly, and cone loss results in legal blindness. It is critical for the function of mammalian cones as daytime photoreceptors that they regenerate their visual pigment rapidly following its destruction by light. This is made possible by two pathways. The canonical retinal pigment epithelium (RPE) visual cycle provides 11-cis retinal chromophore to both rods and cones. In contrast, the novel retina visual cycle relies on Muller cells to provide 11- cis retinol, which can be utilized only by cones after they oxidize it to 11-cis retinal by an unknown dehydrogenase. As we demonstrated over the past five years, the retina visual cycle plays a crucial role in daytime vision by extending the functional range of cones to bright light and by driving their rapid dark adaptation. The scarcity of cones in the mammalian retina makes molecular and biochemical cone-specific studies extremely challenging. As a result, the molecular mechanism that enables cones, but not rods, to use the retina visual cycle is not understood. The mutant rd7 mouse, which lacks the rod transcription factor Nr2e3 and has rods that in addition to its rod genes express a subset of cone genes, provides us with a unique opportunity to identify the molecular mechanism controlling access to the retina visual cycle. The central hypothesis of this proposal is that the molecular properties of photoreceptors control their ability to use the retina visual cycle. Specifically, we will demonstrate that the expressionof a subset of cone genes in the rd7 rods is sufficient to enable them to use 11-cis retinol for pigment regeneration and to access the retina visual cycle. Expression analysis of rd7 rods has allowed us to identify retinol dehydrogenase 10 (RDH10) as a cone-specific gene and the likely key enzyme that oxidizes 11-cis retinol as part of the retina visual cycle. We will use loss and gain of function mutant mice to demonstrate the role of RDH10 in the retina visual cycle. Collectively, the experiments outlined here will identify the molecular mechanism that enables cones to access the retina visual cycle and regenerate rapidly their visual pigment, a property that is critical for daytime, cone-mediated vision in bright and rapidly changing light conditions. They will also provide new therapeutic tools for the treatment of visual disorders caused by faulty RPE visual cycle.

Public Health Relevance

The experiments outlined in this proposal seek to identify the molecular mechanism that enables mammalian cones to function in bright light, an essential property for the photoreceptors that mediate daytime vision. These studies will help us understand the mechanisms that regulate mammalian cone function under normal and pathological conditions and might also provide new therapeutic tools for the treatment of visual disorders caused by deficient RPE visual cycle.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY019312-07
Application #
8891428
Study Section
Biology of the Visual System Study Section (BVS)
Program Officer
Neuhold, Lisa
Project Start
2008-12-01
Project End
2018-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
7
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Washington University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Vinberg, Frans; Chen, Jeannie; Kefalov, Vladimir J (2018) Regulation of calcium homeostasis in the outer segments of rod and cone photoreceptors. Prog Retin Eye Res 67:87-101
Sato, Shinya; Peshenko, Igor V; Olshevskaya, Elena V et al. (2018) GUCY2D Cone-Rod Dystrophy-6 Is a ""Phototransduction Disease"" Triggered by Abnormal Calcium Feedback on Retinal Membrane Guanylyl Cyclase 1. J Neurosci 38:2990-3000
Vinberg, Frans; Kefalov, Vladimir J (2018) Investigating the Ca2+-dependent and Ca2+-independent mechanisms for mammalian cone light adaptation. Sci Rep 8:15864
Kiser, Philip D; Zhang, Jianye; Sharma, Aditya et al. (2018) Retinoid isomerase inhibitors impair but do not block mammalian cone photoreceptor function. J Gen Physiol 150:571-590
Vinberg, Frans; Peshenko, Igor V; Chen, Jeannie et al. (2018) Guanylate cyclase-activating protein 2 contributes to phototransduction and light adaptation in mouse cone photoreceptors. J Biol Chem 293:7457-7465
Xue, Yunlu; Sato, Shinya; Razafsky, David et al. (2017) The role of retinol dehydrogenase 10 in the cone visual cycle. Sci Rep 7:2390
Potter, Chloe; Zhu, Wanqiu; Razafsky, David et al. (2017) Multiple Isoforms of Nesprin1 Are Integral Components of Ciliary Rootlets. Curr Biol 27:2014-2022.e6
Sato, Shinya; Frederiksen, Rikard; Cornwall, M Carter et al. (2017) The retina visual cycle is driven by cis retinol oxidation in the outer segments of cones. Vis Neurosci 34:E004
Vinberg, Frans; Wang, Tian; De Maria, Alicia et al. (2017) The Na+/Ca2+, K+ exchanger NCKX4 is required for efficient cone-mediated vision. Elife 6:
Kolesnikov, Alexander V; Orban, Tivadar; Jin, Hui et al. (2017) Dephosphorylation by protein phosphatase 2A regulates visual pigment regeneration and the dark adaptation of mammalian photoreceptors. Proc Natl Acad Sci U S A 114:E9675-E9684

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