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.
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.
|Frederiksen, Rikard; Nymark, Soile; Kolesnikov, Alexander V et al. (2016) Rhodopsin kinase and arrestin binding control the decay of photoactivated rhodopsin and dark adaptation of mouse rods. J Gen Physiol 148:1-11|
|Sakurai, Keisuke; Vinberg, Frans; Wang, Tian et al. (2016) The Na(+)/Ca(2+), K(+) exchanger 2 modulates mammalian cone phototransduction. Sci Rep 6:32521|
|Ding, Xi-Qin; Thapa, Arjun; Ma, Hongwei et al. (2016) The B3 Subunit of the Cone Cyclic Nucleotide-gated Channel Regulates the Light Responses of Cones and Contributes to the Channel Structural Flexibility. J Biol Chem 291:8721-34|
|Sakurai, Keisuke; Chen, Jeannie; Khani, Shahrokh C et al. (2015) Regulation of mammalian cone phototransduction by recoverin and rhodopsin kinase. J Biol Chem 290:9239-50|
|Vinberg, Frans; Wang, Tian; Molday, Robert S et al. (2015) A new mouse model for stationary night blindness with mutant Slc24a1 explains the pathophysiology of the associated human disease. Hum Mol Genet 24:5915-29|
|Ruzycki, Philip A; Tran, Nicholas M; Kefalov, Vladimir J et al. (2015) Graded gene expression changes determine phenotype severity in mouse models of CRX-associated retinopathies. Genome Biol 16:171|
|Vinberg, Frans; Kefalov, Vladimir (2015) Simultaneous ex vivo functional testing of two retinas by in vivo electroretinogram system. J Vis Exp :e52855|
|Zhang, Ning; Tsybovsky, Yaroslav; Kolesnikov, Alexander V et al. (2015) Protein misfolding and the pathogenesis of ABCA4-associated retinal degenerations. Hum Mol Genet 24:3220-37|
|Sarria, Ignacio; Pahlberg, Johan; Cao, Yan et al. (2015) Sensitivity and kinetics of signal transmission at the first visual synapse differentially impact visually-guided behavior. Elife 4:e06358|
|Berkowitz, Bruce A; Kern, Timothy S; Bissig, David et al. (2015) Systemic Retinaldehyde Treatment Corrects Retinal Oxidative Stress, Rod Dysfunction, and Impaired Visual Performance in Diabetic Mice. Invest Ophthalmol Vis Sci 56:6294-303|
Showing the most recent 10 out of 45 publications