The goal of the proposed research is to decipher a diversity of unexplored behavioral roles for rhodopsins in Drosophila melanogaster, and in the major disease vector, Aedes aegypti. The proposed studies build on our recent discovery that a fly rhodopsin (Rh7) acts as a light sensor in a small set of neurons in the brain, where it contributes to circadian photoentrainment. This represents the first function for a rhodopsin in the central brain, despite decades-old reports that rhodopsins are expressed in the brains of many animals, including humans. We propose to bring to bear a wide set of tools to reveal the rhodopsins and signaling proteins employed in the fly brain and eye for circadian photoentrainment and for sleep. We will then leverage our extensive background in flies and our recent expansion into mosquitoes to reveal the mosquito rhodopsins required for circadian photoentrainment and for detecting humans under different light conditions. This goal is important, since mosquitoes rely heavily on vision to identify humans. Yet, there are no molecular genetic studies focusing on vision or rhodopsins in any insect vector. The project?s success will be made possible by our development and application of an extensive suite of in vivo approaches including electrophysiology, behavioral assays, cell biology, molecular genetic approaches, and expertise in creating gene knockouts in Aedes. We propose to capitalize on a transformative technical innovation we have developed to accelerate molecular genetics in mosquitoes.
Aim 1 will test the hypothesis that Rh7 in the fly brain functions in circadian photoentrainment through a signaling cascade distinct from the one used in the compound eye. The experiments will also test the idea that Rh7 confers greater light sensitivity to pacemaker neurons than is possible through Cryptochrome, the other light sensor in the brain.
Aim 2 focuses on illuminating the roles of different rhodopsins in the Drosophila eye and brain on sleep. We will address the concept that two rhodopsins in a small subset of photoreceptor cells in the compound eye are required for normal nighttime sleep, while Rh7 in the brain affects daytime sleep.
In Aim 3, we will decipher roles for rhodopsins in Aedes that are required for increased visual attraction to humans, following exposure to CO2. We will clarify which rhodopsins are most important for host recognition at different intensities of light. Finally, we will unravel roles for two rhodopsins expressed in the Aedes brain. In summary, the proposed project will deepen our understanding of visual and non-visual rhodopsins that function in circadian photoentrainment and sleep. These are important goals, since our understanding of the mechanisms underlying sleep is rudimentary, and many diseases are exacerbated by impairments in this evolutionarily conserved behavior. Finally, given the importance of mosquito vision for identifying humans, we propose that unraveling the rhodopsins that contribute to human recognition offers to lead to creative CRISPR/Cas9-based approaches to control insect vectors and reduce disease.

Public Health Relevance

One of the goals of this project is to define the impacts of different light receptors, called rhodopsins, on setting circadian rhythms and for normal sleep patterns. The insights gleaned from this work have potential to provide insights into diseases that are exacerbated by impairments in circadian rhythms and sleep. A second goal of this project is to define the rhodopsins in mosquitoes that are most important for recognition of humans, with the long-term goal of devising new strategies to interfere with the attraction of mosquitoes to humans and reduce insect borne disease.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Molecular and Integrative Signal Transduction Study Section (MIST)
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Greenwell, Thomas
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University of California Santa Barbara
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Santa Barbara
United States
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Liu, Jiangqu; Sokabe, Takaaki; Montell, Craig (2018) A Temperature Gradient Assay to Determine Thermal Preferences of Drosophila Larvae. J Vis Exp :
Leung, Nicole Y; Montell, Craig (2017) Unconventional Roles of Opsins. Annu Rev Cell Dev Biol 33:241-264
Ni, Jinfei D; Baik, Lisa S; Holmes, Todd C et al. (2017) A rhodopsin in the brain functions in circadian photoentrainment in Drosophila. Nature 545:340-344
Sokabe, Takaaki; Chen, Hsiang-Chin; Luo, Junjie et al. (2016) A Switch in Thermal Preference in Drosophila Larvae Depends on Multiple Rhodopsins. Cell Rep 17:336-344
Hofmann, Lukas; Tsybovsky, Yaroslav; Alexander, Nathan S et al. (2016) Structural Insights into the Drosophila melanogaster Retinol Dehydrogenase, a Member of the Short-Chain Dehydrogenase/Reductase Family. Biochemistry 55:6545-6557
Walker, Marquis T; Montell, Craig (2016) Suppression of the motor deficit in a mucolipidosis type IV mouse model by bone marrow transplantation. Hum Mol Genet 25:2752-2761
Walker, Marquis T; Rupp, Alan; Elsaesser, Rebecca et al. (2015) RdgB2 is required for dim-light input into intrinsically photosensitive retinal ganglion cells. Mol Biol Cell 26:3671-8
Chen, Zijing; Chen, Hsiang-Chin; Montell, Craig (2015) TRP and Rhodopsin Transport Depends on Dual XPORT ER Chaperones Encoded by an Operon. Cell Rep 13:573-584
Liu, Chao; Montell, Craig (2015) Forcing open TRP channels: Mechanical gating as a unifying activation mechanism. Biochem Biophys Res Commun 460:22-5
Akitake, Bradley; Ren, Qiuting; Boiko, Nina et al. (2015) Coordination and fine motor control depend on Drosophila TRP?. Nat Commun 6:7288

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