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Melanopsin and rod–cone photoreceptive systems account for all major accessory visual functions in mice

Abstract

In the mammalian retina, besides the conventional rod–cone system, a melanopsin-associated photoreceptive system exists that conveys photic information for accessory visual functions such as pupillary light reflex and circadian photo-entrainment1,2,3,4,5,6,7. On ablation of the melanopsin gene, retinal ganglion cells that normally express melanopsin are no longer intrinsically photosensitive8. Furthermore, pupil reflex8, light-induced phase delays of the circadian clock9,10 and period lengthening of the circadian rhythm in constant light9,10 are all partially impaired. Here, we investigated whether additional photoreceptive systems participate in these responses. Using mice lacking rods and cones, we measured the action spectrum for phase-shifting the circadian rhythm of locomotor behaviour. This spectrum matches that for the pupillary light reflex in mice of the same genotype11, and that for the intrinsic photosensitivity of the melanopsin-expressing retinal ganglion cells7. We have also generated mice lacking melanopsin coupled with disabled rod and cone phototransduction mechanisms. These animals have an intact retina but fail to show any significant pupil reflex, to entrain to light/dark cycles, and to show any masking response to light. Thus, the rod–cone and melanopsin systems together seem to provide all of the photic input for these accessory visual functions.

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Figure 1: Irradiance–response relations (a) and action spectrum (b) for circadian phase shifting in rd/rd cl mice by monochromatic light between 420 nm and 580 nm, assayed by wheel-running (n = 4–7 animals per irradiance at each wavelength).
Figure 2: Normal retinal morphology and presence and central connectivity of melanopsin-expressing RGCs in triple-knockout (Opn4-/- Gnat1-/- Cnga3-/-) mice.
Figure 3: Disabling of rods, cones and melanopsin-positive RGCs essentially eliminates the pupillary light reflex.
Figure 4: Actograms of wheel running for mice under a 16/8-h light/dark cycle, double-plotted on a 24-h timescale.
Figure 5: Actograms of wheel running plotted on a 7-h timescale.

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References

  1. Provencio, I., Jiang, G., DeGrip, 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 

  2. Provencio, I. et al. A novel human opsin in the inner retina. J. Neurosci. 20, 600–605 (2000)

    Article  CAS  Google Scholar 

  3. Gooley, J. J., Lu, J., Chou, T. C., Scammell, T. E. & Saper, C. B. Melanopsin in cells of origin of the retinohypothalamic tract. Nature Neurosci. 4, 1165 (2001)

    Article  CAS  Google Scholar 

  4. Hannibal, J., Hindersson, P., Knudsen, S. M., Georg, B. & Fahrenkrug, J. The photopigment melanopsin is exclusively present in pituitary adenylate cyclase-activating polypeptide-containing retinal ganglion cells of the retinohypothalamic tract. J. Neurosci. 22, RC191 (2002)

    Article  Google Scholar 

  5. Provencio, I., Rollag, M. D. & Castrucci, A. M. Photoreceptive net in the mammalian retina. Nature 415, 493 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  6. 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  PubMed  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  8. 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 

  9. Panda, S. et al. Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting. Science 298, 2213–2216 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  10. Ruby, N. F. et al. Role of melanopsin in circadian responses to light. Science 298, 2211–2213 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  11. Lucas, R. J., Douglas, R. H. & Foster, R. G. Characterization of an ocular photopigment capable of driving pupillary constriction in mice. Nature Neurosci. 4, 621–626 (2001)

    Article  CAS  PubMed  Google Scholar 

  12. Emery, P., So, W. V., Kaneko, M., Hall, J. C. & Rosbash, M. CRY, a Drosophila clock and light-regulated cryptochrome, is a major contributor to circadian rhythm resetting and photosensitivity. Cell 95, 669–679 (1998)

    Article  CAS  PubMed  Google Scholar 

  13. Ceriani, M. F. et al. Light-dependent sequestration of TIMELESS by CRYPTOCHROME. Science 285, 553–556 (1999)

    Article  CAS  PubMed  Google Scholar 

  14. Selby, C. P., Thompson, C., Schmitz, T. M., van Gelder, R. N. & Sancar, A. Functional redundancy of cryptochromes and classical photoreceptors for nonvisual ocular photoreception in mice. Proc. Natl Acad. Sci. USA 97, 14697–14702 (2000)

    Article  ADS  CAS  PubMed  Google Scholar 

  15. van Gelder, R. N. Non-visual ocular photoreception. Ophthalmic Genet. 22, 195–205 (2001)

    Article  CAS  Google Scholar 

  16. van Gelder, R. N., Wee, R., Lee, J. A. & Tu, D. C. Reduced pupillary light responses in mice lacking cryptochromes. Science 299, 222 (2003)

    Article  CAS  Google Scholar 

  17. Griffin, E. A. Jr, Staknis, D. & Weitz, C. J. Light-independent role of CRY1 and CRY2 in the mammalian circadian clock. Science 286, 768–771 (1999)

    Article  CAS  PubMed  Google Scholar 

  18. Lucas, R. J., Freedman, M. S., Munoz, M., Garcia-Fernandez, J. M. & Foster, R. Regulation of the mammalian pineal by non-rod, non-cone, ocular photoreceptors. Science 284, 505–507 (1999)

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Calvert, P. D. et al. Phototransduction in transgenic mice after targeted deletion of the rod transducin α-subunit. Proc. Natl Acad. Sci. USA 97, 13913–13918 (2000)

    Article  ADS  CAS  Google Scholar 

  20. Biel, M. et al. Selective loss of cone function in mice lacking the cyclic nucleotide-gated channel CNG3. Proc. Natl Acad. Sci. USA 96, 7553–7557 (1999)

    Article  ADS  CAS  Google Scholar 

  21. Bradley, J., Frings, S., Yau, K.-W. & Reed, R. Nomenclature for ion channel subunits. Science 294, 2095–2096 (2001)

    Article  CAS  PubMed  Google Scholar 

  22. Cone, R. A. Early receptor potential: photoreversible charge displacement in rhodopsin. Science 155, 1128–1131 (1967)

    Article  ADS  CAS  Google Scholar 

  23. Murakami, M. & Pak, W. L. Intracellularly recorded early receptor potential of the vertebrate photoreceptors. Vision Res. 10, 965–975 (1970)

    Article  CAS  Google Scholar 

  24. Brockerhoff, S. E. et al. Light stimulates a transducin-independent increase of cytoplasmic Ca2+ and suppression of current in cones from the zebrafish mutant nof. J. Neurosci. 23, 470–480 (2003)

    Article  CAS  Google Scholar 

  25. Wee, R., Castrucci, A. M., Provencio, I., Gan, L. & van Gelder, R. N. Loss of photic entrainment and altered free-running circadian rhythms in math5-/- mice. J. Neurosci. 22, 10427–10433 (2002)

    Article  CAS  Google Scholar 

  26. Aschoff, J. in Trends in Chronobiology. Advances in the Biosciences Vol. 73 (eds Hekkens, W. T. J. M., Kerkhof, G. A. & Rietveld, W. J.) 149–161 (Pergamon, Oxford, 1988)

    Google Scholar 

  27. Mrosovsky, N. Masking: history, definitions, and measurement. Chronobiol. Int. 16, 415–429 (1999)

    Article  CAS  Google Scholar 

  28. Mrosovsky, N., Lucas, R. J. & Foster, R. G. Persistence of masking responses to light in mice lacking rods and cones. J. Biol. Rhythms 16, 585–587 (2001)

    Article  CAS  Google Scholar 

  29. Redlin, U. & Mrosovsky, N. Masking of locomotor activity in hamsters. J. Comp. Physiol. A 184, 429–437 (1999)

    Article  CAS  Google Scholar 

  30. Mrosovsky, N. Further characterization of the phenotype of mCry1/mCry2-deficient mice. Chronobiol. Int. 18, 613–625 (2001)

    Article  CAS  Google Scholar 

  31. Yoshimura, T. & Ebihara, S. Spectral sensitivity of photoreceptors mediating phase-shifts of circadian rhythms in retinally degenerate CBA/J (rd/rd) and normal CBA/N (+ / + ) mice. J. Comp. Physiol. A 178, 797–802 (1996)

    Article  CAS  PubMed  Google Scholar 

  32. Provencio, I. & Foster, R. G. Circadian rhythms in mice can be regulated by photoreceptors with cone-like characteristics. Brain Res. 694, 183–190 (1995)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank H.-W. Liao and J. Lai for help in performing the immunocytochemical experiments with antibodies against cryptochromes; J. Butler for help with real-time RT–PCR; Y. Liang for help in genotyping the animals; P. Salmon for help in the wheel-running experiments; and D. M. Berson, H. R. Matthews, G. L. Fain and members of the Yau laboratory for scientific discussions. This work was supported by the US National Eye Institute (K.-W.Y.), the UK Biotechnology and Biological Sciences Research Council and the Wellcome Trust (R.J.L. and R.G.F.), and the Canadian Institutes of Health Research (N.M.).

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Correspondence to K.-W. Yau.

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Hattar, S., Lucas, R., Mrosovsky, N. et al. Melanopsin and rod–cone photoreceptive systems account for all major accessory visual functions in mice. Nature 424, 75–81 (2003). https://doi.org/10.1038/nature01761

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