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Neuropsin (OPN5)-Mediated Photoentrainment of Local Circadian Oscillators in Mammalian Retina and Cornea

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Neuropsin (OPN5)-Mediated Photoentrainment of Local Circadian Oscillators in Mammalian Retina and Cornea Neuropsin (OPN5)-mediated photoentrainment of local circadian oscillators in mammalian retina and cornea Ethan D. Buhra, Wendy W. S. Yueb, Xiaozhi Renb, Zheng Jiangb, Hsi-Wen Rock Liaob,1, Xue Meic, Shruti Vemarajuc, Minh-Thanh Nguyenc, Randall R. Reedd,e, Richard A. Langc,f, King-Wai Yaub,e,g,2, and Russell N. Van Geldera,h,i,2 aDepartment of Ophthalmology, University of Washington Medical School, Seattle, WA 98104; bThe Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205; cVisual Systems Group, Abrahamson Pediatric Eye Institute, Division of Pediatric Ophthalmology and Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229; dDepartment of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205; eCenter for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; fDepartment of Ophthalmology, University of Cincinnati Medical Center, Cincinnati, OH 45229; gDepartment of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; hDepartment of Biological Structure, University of Washington Medical School, Seattle, WA 98104; and iDepartment of Pathology, University of Washington Medical School, Seattle, WA 98104 Contributed by King-Wai Yau, August 17, 2015 (sent for review July 22, 2015; reviewed by Carla B. Green and Christophe P. Ribelayga) The molecular circadian clocks in the mammalian retina are locally opsin (23) and peropsin (RRH) (24). RGR opsin participates in synchronized by environmental light cycles independent of the retinoid turnover (25, 26), whereas RRH is expressed princi- suprachiasmatic nuclei (SCN) in the brain. Unexpectedly, this entrain- pally in the retinal pigment epithelium (24), a cell layer absent ment does not require rods, cones, or melanopsin (OPN4), possibly in the photoentrainable ex vivo retina preparation (7). suggesting the involvement of another retinal photopigment. Here, we show that the ex vivo mouse retinal rhythm is most sensitive Results to short-wavelength light but that this photoentrainment requires Wavelength Dependence of ex Vivo Retinal Circadian Photoentrainment. neither the short-wavelength–sensitive cone pigment [S-pigment We first examined the wavelength dependence of retinal circadian or cone opsin (OPN1SW)] nor encephalopsin (OPN3). However, ret- photoentrainment with Per2::Luciferase mouse retinas (27). The inas lacking neuropsin (OPN5) fail to photoentrain, even though luciferase luminescence from these retinas comes predominantly other visual functions appear largely normal. Initial evidence sug- from the inner retina (28, 29), although autonomous rhythms have gests that OPN5 is expressed in select retinal ganglion cells. Remark- also been found in the outer retina (28). Pairs of retinas from these ably, the mouse corneal circadian rhythm is also photoentrainable mice were exposed ex vivo to 9-h/15-h light/dark cycles for 4 d, with ex vivo, and this photoentrainment likewise requires OPN5. Our the two retinas in each pair subjected to opposite-phase light/dark findings reveal a light-sensing function for mammalian OPN5, entrainment (7) (SI Materials and Methods). Immediately after until now an orphan opsin. cyclic light exposure, the luciferase luminescence in each retina was measured for 4 d in continuous darkness to determine the circadian OPN5 | photoentrainment | circadian rhythm | retina | cornea phase. In previous work with white light (7), paired retinas under these conditions showed opposite phases, with peak luminescence ost mammalian tissues contain autonomous circadian clocks occurring at roughly 4 h after the respective light-to-dark transition. Mthat are synchronized by the suprachiasmatic nuclei (SCN) in To determine wavelength dependence, we replaced white light the brain (1). The SCN clock itself is entrained by external light cycles with monochromatic light-emitting–diode light at 370 nm, 417 nm, through retinal rods, cones, and melanopsin (OPN4)-expressing, 475 nm, 530 nm, or 628 nm; peak photon flux at each of the last intrinsically photosensitive retinal ganglion cells (ipRGCs) (2, 3). The retina also manifests a local circadian clock, which regulates Significance many important functions, such as photoreceptor disk shedding, photoreceptor gap-junction coupling, and neurotransmitter re- NEUROSCIENCE lease (4–6). Surprisingly, local retinal photoentrainment does not The behavioral circadian rhythms of mammals are synchronized require the SCN, and it also does not require rods, cones, or to light/dark cycles through rods, cones, and melanopsin (OPN4)- − − ipRGCs (7, 8). Thus, the rd1/rd1;Opn4 / mouse retina, which has expressing, intrinsically photosensitive ganglion cells in the ret- lost essentially all rods and cones due to degeneration and also has ina. The molecular circadian rhythms in the mammalian retina an ablated Opn4 gene (3), remains synchronized to light/dark cy- are themselves synchronized to light/dark signals. We show here cles both in vivo and ex vivo (7). that this retinal photoentrainment, in an ex vivo setting, requires To determine the photopigment(s) responsible for local circa- neuropsin (OPN5), an orphan opsin in mammals. Remarkably, the dian entrainment in the retina, we took a candidate gene approach. circadian clocks in the cornea are also photoentrained ex vivo in an OPN5-dependent manner. Because some cone nuclei may persist in degenerate rd1/rd1 retinas (9), and murine short-wavelength–sensitive cone opsin (OPN1SW) Author contributions: E.D.B. and R.N.V.G. designed and performed all photoentrainment − − − − hasbeenreportedtobepresentintheganglioncelllayer(10),we experiments; H.-W.R.L. made the Opn5 / line 1; W.W.S.Y. characterized the Opn5 / line tested the necessity of this pigment for local retinal circadian 1; X.R. generated the Opn3−/− mouse line; W.W.S.Y. performed the X-Gal labelings − − photoentrainment. We also tested for the involvement of two or- (Opn5 / line 1) and immunolabelings (line 1); S.V. performed the X-Gal labelings (line 2); W.W.S.Y. and Z.J. performed the CMFDG labeling and subsequent injection of Alexa phan pigments, encephalopsin (OPN3) (11) and neuropsin (OPN5) dyes (line 1); R.R.R. provided invaluable advice on molecular biology and genetics; X.M., − − (12), both of which are expressed in mammalian retina and, when S.V., M.-T.N., and R.A.L generated and characterized the Opn5 / line 2; and E.D.B., W.W.S.Y., expressed heterologously, form light-sensitive pigments that acti- R.A.L., K.-W.Y., and R.N.V.G wrote the paper. vate G proteins (13–17). The function of OPN3 in mammals is Reviewers: C.B.G., University of Texas Southwestern Medical Center; and C.P.R., University unknown despite its widespread expression in neural tissues (18). of Texas Health Science Center at Houston. OPN5 appears to be a deep-brain photopigment in the hypothal- The authors declare no conflict of interest. amus of birds and is thought to contribute to seasonal reproduction Freely available online through the PNAS open access option. (19–22); it has been immunolocalized to the mammalian inner 1Present address: Department of Neurobiology, Harvard Medical School, Boston, MA 02115. retina (13, 16) (SI Text); however, to date, no retinal function for 2To whom correspondence may be addressed. Email: [email protected] or [email protected]. this mammalian pigment has been identified. We did not examine This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. two other pigments, retinal G protein-coupled receptor (RGR) 1073/pnas.1516259112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1516259112 PNAS | October 20, 2015 | vol. 112 | no. 42 | 13093–13098 Downloaded by guest on September 27, 2021 − − four wavelengths was identical (9 × 1013 photons cm 2·s 1) but was Per2::Luciferase) did (Fig. 1C). Furthermore, in response to an − − 10-fold less (9 × 1012 photons cm 2·s 1) at 370 nm to avoid tissue acute violet light pulse (3 h, 417 nm) of various intensities ad- − − toxicity at higher UV intensities. After 4 d of entrainment, the ministered at circadian time (CT) 9 or CT 20, Opn1sw / ;Per2:: paired retinas exposed to 370-nm light/dark cycles had stable, nearly Luciferase retinas phase-shifted with sensitivity identical to the sen- opposite entrainment phases, as did retinas exposed to 417-nm sitivity of WT retinas (Fig. 1D). The quantitatively similar photo- − − light/dark cycles (Fig. 1A). In contrast, the paired retinas exposed to sensitivities exhibited by WT and Opn1sw / retinas to violet light 475-nm light/dark cycles showed only a moderate, ∼6-h difference demonstrate that OPN1SW is not required for retinal photo- in their phases. Paired retinas exposed to 530-nm or 628-nm light/ entrainment ex vivo. dark cycles did not photoentrain, with each having phases identical to retinas kept in continuous darkness (Fig. 1A, rightmost vertical OPN5, but Not OPN3, Is Required for ex Vivo Retinal Photoentrainment. λ bar). Thus, circadian photoentrainment in ex vivo retinas is most Mouse OPN5 has a max in the UV-A region (380 nm) when sensitive to UV-A and violet light. heterologously expressed (13, 16). For OPN3, heterologously λ To confirm this spectral sensitivity, we tested retinas for acute expressed fish and insect homologs have a max of 460 nm and λ phase shifts under different wavelengths. Per2::Luciferase ret- 500 nm, respectively (14), but the max of mammalian OPN3 is still inas were cultured in continuous darkness. At different phases unknown. We examined both OPN3 and OPN5 with the gene KO −/− −/− −/− during their free-running circadian rhythms, we administered approach. We generated Opn3 and Opn5 (“Opn5 line 1”) equal quanta of a 3-h light pulse at 417 nm or 475 nm and mea- mice by homologous recombination (SI Materials and Methods and sured the resulting phase delay or phase advance in the rhythm to Fig. S1 A and B). We bred these lines into the Per2::Luciferase line generate a phase-response curve. At all phases, 417-nm light to perform ex vivo photoentrainment experiments (retinas cul- triggered phase shifts that were consistently larger than those tured for 4 d under 9-h/15-h white light/dark cycles).
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