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Melanopsin signalling in mammalian iris and retina

Abstract

Non-mammalian vertebrates have an intrinsically photosensitive iris and thus a local pupillary light reflex (PLR). In contrast, it is thought that the PLR in mammals generally requires neuronal circuitry connecting the eye and the brain. Here we report that an intrinsic component of the PLR is in fact widespread in nocturnal and crepuscular mammals. In mouse, this intrinsic PLR requires the visual pigment melanopsin; it also requires PLCβ4, a vertebrate homologue of the Drosophila NorpA phospholipase C which mediates rhabdomeric phototransduction. The Plcb4−/− genotype, in addition to removing the intrinsic PLR, also essentially eliminates the intrinsic light response of the M1 subtype of melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (M1-ipRGCs), which are by far the most photosensitive ipRGC subtype and also have the largest response to light. Ablating in mouse the expression of both TRPC6 and TRPC7, members of the TRP channel superfamily, also essentially eliminated the M1-ipRGC light response but the intrinsic PLR was not affected. Thus, melanopsin signalling exists in both iris and retina, involving a PLCβ4-mediated pathway that nonetheless diverges in the two locations.

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Figure 1: Intrinsic PLR of mouse.
Figure 2: Intrinsic photosensitivity of iris sphincter muscle of other mammals.
Figure 3: Dependence of intrinsic PLR on melanopsin.
Figure 4: Phototransduction mechanism underlying intrinsic PLR.
Figure 5: Phototransduction mechanism and components underlying ipRGC intrinsic light response.
Figure 6: Simultaneous direct (ipsilateral) and consensual (contralateral) PLRs to unilateral illumination for different mouse genotypes in situ.

References

  1. Berson, D. M., Dunn, F. A. & Takao, M. Phototransduction by retinal ganglion cells that set the circadian clock. Science 295, 1070–1073 (2002)

    Article  ADS  CAS  Google Scholar 

  2. Hattar, S., Liao, H.-W., Takao, M., Berson, D. M. & Yau, K.-W. Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science 295, 1065–1070 (2002)

    Article  ADS  CAS  Google Scholar 

  3. Bailes, H. J. & Lucas, R. J. Melanopsin and inner retinal photoreception. Cell. Mol. Life Sci. 67, 99–111 (2010)

    Article  CAS  Google Scholar 

  4. Do, M. T. H. & Yau, K.-W. Intrinsically photosensitive retinal ganglion cells. Physiol. Rev. 90, 1547–1581 (2010)

    Article  CAS  Google Scholar 

  5. Hankins, M. W., Peirson, S. N. & Foster, R. G. Melanopsin: an exciting photopigment. Trends Neurosci. 31, 27–36 (2008)

    Article  CAS  Google Scholar 

  6. Nayak, S. K., Jegla, T. & Panda, S. Role of a novel photopigment, melanopsin, in behavioral adaptation to light. Cell. Mol. Life Sci. 64, 144–154 (2007)

    Article  CAS  Google Scholar 

  7. Barr, L. Photomechanical coupling in the vertebrate sphincter papillae. Crit. Rev. Neurobiol. 4, 325–366 (1989)

    CAS  PubMed  Google Scholar 

  8. Seliger, H. H. Direct action of light in naturally pigmented muscle fibers. I. Action spectrum for contraction in eel iris sphincter. J. Gen. Physiol. 46, 333–342 (1962)

    Article  CAS  Google Scholar 

  9. Barr, L. & Alpern, M. Photosensitivity of the frog iris. J. Gen. Physiol. 46, 1249–1265 (1963)

    Article  CAS  Google Scholar 

  10. Kargacin, G. J. & Detwiler, P. B. Light-evoked contraction of the photosensitive iris of the frog. J. Neurosci. 5, 3081–3087 (1985)

    Article  CAS  Google Scholar 

  11. Tu, D. C., Batten, M. L., Palzewski, K. & Van Gelder, R. N. Nonvisual photoreception in the chick iris. Science 306, 129–131 (2004)

    Article  ADS  CAS  Google Scholar 

  12. Bito, L. Z. & Turansky, D. G. Photoactivation of pupillary constriction in the isolated in vitro iris of a mammal (Mesocricetus auratus). Comp. Biochem. Physiol. 50A, 407–413 (1975)

    Article  Google Scholar 

  13. Lau, K. C., So, K.-F., Campbell, G. & Lieberman, A. R. Pupillary constriction in response to light in rodents, which does not depend on central neural pathways. J. Neurol. Sci. 113, 70–79 (1992)

    Article  CAS  Google Scholar 

  14. Oyster, C. W. The Human Eye: Structure and Function (Sinauer, 1999)

    Google Scholar 

  15. Do, M. T. H. et al. Photon capture and signalling by melanopsin retinal ganglion cells. Nature 457, 281–287 (2009)

    Article  ADS  CAS  Google Scholar 

  16. Blanchong, J. A., McElhinny, T. L., Mahoney, M. M. & Smale, L. Nocturnal and diurnal rhythms in the unstriped Nile rat, Arvicanthis niloticus . J. Biol. Rhythms 14, 364–377 (1999)

    Article  CAS  Google Scholar 

  17. Govardovskii, V. I., Fyhrquist, N., Reuter, T., Kuzmin, D. G. & Donner, K. In search of the visual pigment template. Vis. Neurosci. 17, 509–528 (2000)

    Article  CAS  Google Scholar 

  18. Lucas, R. J. et al. Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice. Science 299, 245–247 (2003)

    Article  ADS  CAS  Google Scholar 

  19. Lem, J. et al. Morphological, physiological, and biochemical changes in rhodopsin knockout mice. Proc. Natl Acad. Sci. USA 96, 736–741 (1999)

    Article  ADS  CAS  Google Scholar 

  20. Vitaterna, M. H. et al. Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2. Proc. Natl Acad. Sci. USA 96, 12114–12119 (1999)

    Article  ADS  CAS  Google Scholar 

  21. Ghosh, S., Salvador-Silva, M. & Coca-Prados, M. The bovine iris-ciliary epithelium expresses components of rod phototransduction. Neurosci. Lett. 370, 7–12 (2004)

    Article  CAS  Google Scholar 

  22. Provencio, I., Jiang, G., De Grip, W. J., Hayes, W. P. & Rollag, M. D. Melanopsin: An opsin in melanophores, brain, and eye. Proc. Natl Acad. Sci. USA 95, 340–345 (1998)

    Article  ADS  CAS  Google Scholar 

  23. Yau, K.-W. & Hardie, R. C. Phototransduction motifs and variations. Cell 139, 246–264 (2009)

    Article  CAS  Google Scholar 

  24. Berridge, M. J. Smooth muscle cell calcium activation mechanisms. J. Physiol. 586, 5047–5061 (2008)

    Article  CAS  Google Scholar 

  25. Gonzalez-Cobos, J. C. & Trebak, M. TRPC channels in smooth muscle cells. Front. Biosci. 15, 1023–1039 (2010)

    Article  CAS  Google Scholar 

  26. Jiang, H. et al. Phospholipase C β4 is involved in modulating the visual response in mice. Proc. Natl Acad. Sci. USA 93, 14598–14601 (1996)

    Article  ADS  CAS  Google Scholar 

  27. Suzuki, M., Mizuno, A., Kodaira, K. & Imai, M. Impaired pressure sensation in mice lacking TRPV4. J. Biol. Chem. 278, 22664–22668 (2003)

    Article  CAS  Google Scholar 

  28. Zucker, R. & Nolte, J. Light-induced calcium release in a photosensitive vertebrate smooth muscle. Nature 274, 78–80 (1978)

    Article  ADS  CAS  Google Scholar 

  29. Graham, D. M. et al. Melanopsin ganglion cells use a membrane-associated rhabdomeric phototransduction cascade. J. Neurophysiol. 99, 2522–2532 (2008)

    Article  CAS  Google Scholar 

  30. Venkatachalam, K. & Montell, C. TRP channels. Annu. Rev. Biochem. 76, 387–417 (2007)

    Article  CAS  Google Scholar 

  31. Hattar, S. et al. Melanopsin and rod-cone photoreceptive systems account for all major accessory visual functions in mice. Nature 424, 75–81 (2003)

    Article  ADS  Google Scholar 

  32. Allen, A. E., Cameron, M. A., Brown, T. M., Vugler, A. A. & Lucas, R. J. Visual responses in mice lacking critical components of all known retinal phototransduction cascades. PLoS ONE 5, e15063 (2010)

    Article  ADS  CAS  Google Scholar 

  33. Organisciak, D. T. & Vaughan, D. K. Retinal light damage: Mechanisms and protection. Prog. Retin. Eye Res. 29, 113–134 (2010)

    Article  Google Scholar 

  34. Grozdanic, S. et al. Characterization of the pupil light reflex, electroretinogram and tonometric parameters in healthy mouse eyes. Curr. Eye Res. 26, 371–378 (2003)

    Article  Google Scholar 

  35. Zhu, Y. et al. Melanopsin-dependent persistence and photopotentiation of murine pupillary light responses. Invest. Ophthalmol. Vis. Sci. 48, 1268–1275 (2007)

    Article  Google Scholar 

  36. Bellingham, J., Whitmore, D., Philp, A. R., Wells, D. J. & Foster, R. G. Zebrafish melanopsin: isolation, tissue localisation and phylogenetic position. Brain Res. Mol. Brain Res. 107, 128–136 (2002)

    Article  CAS  Google Scholar 

  37. Chaurasia, S. S. et al. Molecular cloning, localization and circadian expression of chicken melanopsin (Opn4): differential regulation of expression in pineal and retinal cell types. J. Neurochem. 92, 158–170 (2005)

    Article  CAS  Google Scholar 

  38. Panda, S. et al. Illumination of the melanopsin signaling pathway. Science 307, 600–604 (2005)

    Article  ADS  CAS  Google Scholar 

  39. Qiu, X. et al. Induction of photosensitivity by heterologous expression of melanopsin. Nature 433, 745–749 (2005)

    Article  ADS  CAS  Google Scholar 

  40. Isoldi, M. C., Rollag, M. D., Castrucci, A. M. & Provencio, I. Rhabdomeric phototransduction initiated by the vertebrate photopigment melanopsin. Proc. Natl Acad. Sci. USA 102, 1217–1221 (2005)

    Article  ADS  CAS  Google Scholar 

  41. Gomez, M., del P, Angueyra, J. M. & Nasi, E. Light-transduction in melanopsin-expressing photoreceptors of Amphioxus. Proc. Natl Acad. Sci. USA 106, 9081–9086 (2009)

    Article  ADS  Google Scholar 

  42. Koyanagi, M., Kubokawa, K., Tsukamoto, H., Shichida, Y. & Terakita, A. Cephalochordate melanopsin: evolutionary linkage between invertebrate visual cells and vertebrate photosensitive retinal ganglion cells. Curr. Biol. 15, 1065–1069 (2005)

    Article  CAS  Google Scholar 

  43. Warren, E. J., Allen, C. N., Brown, R. L. & Robinson, D. W. The light-activated signaling pathway in SCN-projecting rat retinal ganglion cells. Eur. J. Neurosci. 23, 2477–2487 (2006)

    Article  Google Scholar 

  44. Sekaran, S. et al. 2-Aminoethoxydiphenylborane is an acute inhibitor of directly photosensitive retinal ganglion cell activity in vitro and in vivo . J. Neurosci. 27, 3981–3986 (2007)

    Article  CAS  Google Scholar 

  45. Hartwick, A. T. et al. Light-evoked calcium responses of isolated melanopsin-expressing retinal ganglion cells. J. Neurosci. 27, 13468–13480 (2007)

    Article  CAS  Google Scholar 

  46. Terakita, A. et al. Expression and comparative characterization of Gq-coupled invertebrate visual pigments and melanopsin. J. Neurochem. 105, 883–890 (2008)

    Article  CAS  Google Scholar 

  47. Lin, B., Koizumi, A., Tanaka, N., Panda, S. & Masland, R. H. Restoration of visual function in retinal degeneration mice by ectopic expression of melanopsin. Proc. Natl Acad. Sci. USA 105, 16009–16014 (2008)

    Article  ADS  CAS  Google Scholar 

  48. Peng, Y. W. et al. Identification of components of a phosphoinositide signaling pathway in retinal rod outer segments. Proc. Natl Acad. Sci. USA 94, 1995–2000 (1997)

    Article  ADS  CAS  Google Scholar 

  49. Perez-Leighton, C. E., Schmidt, T. M., Abramowitz, J., Birnbaumer, L. & Kofuji, P. Intrinsic phototransduction persists in melanopsin-expressing ganglion cells lacking diacylglycerol-sensitive TRPC subunits. Eur. J. Neurosci. 33, 856–867 (2011)

    Article  Google Scholar 

  50. Cahill, H. & Nathans, J. The optokinetic reflex as a tool for quantitative analyses of nervous system function in mice: application to genetic and drug-induced variation. PLoS ONE 3, e2055 (2008)

    Article  ADS  Google Scholar 

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Acknowledgements

We thank the following individuals for providing knockout mouse lines: M. Caterina (Trpv4−/−), J. Lem (Rho−/− and Gnat1−/−), J. C. Chen (Rho−/−), J. Nathans (cl, also known as cone-DTA), A. Sancar (Cry1−/−Cry2−/− ) and L. Birnbaumer (Trpc1−/−, Trpc3−/− and Trpc6−/−). We thank D. Marshak, R. von der Heydt, X. Wang and V. Casagrande for eyes from baboon, rhesus monkey, marmoset and bush baby, respectively, and W. Li, R. Mi, B. O’Rourke, L. Pipitone, D. Ruben, D. Ryugo, L. Smale and G. Tomaselli for eyes of other animals. Experiments on bush baby were carried out in the Casagrande laboratory with help and hospitality. We also thank W. Gao for suggestions on the force transducer, F. Rieke and A. Sampath for suggestions on the design of the LED light system, P. Ala-Laurila for the method of equivalent 480-nm-photon conversion, H. Cahill for the mouse-head-anchoring method, X. Ren for help on western blots, O. Garalde and A. Chen for help in the monkey experiments, and W. W. S. Yue for help on RT–PCR. We also thank T. Shelley for fabricating all custom equipment, S. Kulason for help in data analysis, and L. Ding for mouse-genotyping support. Members of the Yau laboratory provided comments on the manuscript. This work was supported by US NIH Grant EY14596 and the António Champalimaud Vision Award (Portugal) to K.-W.Y.

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T.X., M.T.H.D. and K.-W.Y. designed the experiments. T.X. and M.T.H.D. did the isolated-eyeball experiments. T.X. carried out all muscle recordings and also Trpc knockout ipRGC recordings at 23 °C (recordings at 35°C were by Z.J.), the mouse-optic-nerve transections, some of the in situ PLR measurements (the rest done by J.H.), some of the RT–PCR experiments on melanopsin (the rest done by H.C.W.), the tdTomato-fluorescence experiments, and the generation and maintenance of all double, triple and quadruple genetically engineered mouse lines for this study. The recordings from ipRGCs of Plcb4−/− mice and their wild-type littermates were done by M.T.H.D. (23 °C) and Z.J. (35 °C). T.X., M.T.H.D. and J.H. designed the head-fixed, dual-PLR-recording instrument. T.X. and H.C.W. did the anterior-chamber measurements. H.C.W. did the immunocytochemistry and X-gal labelling. S.L.M. and D.S.W. did the surgery of transecting the optic nerve in anaesthetized monkeys, and tested the PLR with T.X. and M.T.H.D. T.Y. participated in the monkey experiments. A.R. in D.E.C.’s laboratory made the Trpc7−/− mouse line and did the associated characterization (retinal RT–PCR done by T.X.). P.W., S.S., V.F. and M.F. made the Trpc5−/− line and did the associated characterization, and also provided the Trpc4−/− and Trpc4−/− Trpc5−/− lines. M.I.S. provided the Plcb4−/− line. T.X., M.T.H.D. and Z.J. analysed the data with assistance from J.H., and, together with K.-W.Y., wrote the paper.

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Correspondence to T. Xue or K.-W. Yau.

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Xue, T., Do, M., Riccio, A. et al. Melanopsin signalling in mammalian iris and retina. Nature 479, 67–73 (2011). https://doi.org/10.1038/nature10567

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