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Photoentrainment and pupillary light reflex are mediated by distinct populations of ipRGCs

Nature volume 476, pages 9295 (04 August 2011) | Download Citation

Abstract

Intrinsically photosensitive retinal ganglion cells (ipRGCs) express the photopigment melanopsin and regulate a wide array of light-dependent physiological processes1,2,3,4,5,6,7,8,9,10,11. Genetic ablation of ipRGCs eliminates circadian photoentrainment and severely disrupts the pupillary light reflex (PLR)12,13. Here we show that ipRGCs consist of distinct subpopulations that differentially express the Brn3b transcription factor, and can be functionally distinguished. Brn3b-negative M1 ipRGCs innervate the suprachiasmatic nucleus (SCN) of the hypothalamus, whereas Brn3b-positive ipRGCs innervate all other known brain targets, including the olivary pretectal nucleus. Consistent with these innervation patterns, selective ablation of Brn3b-positive ipRGCs severely disrupts the PLR, but does not impair circadian photoentrainment. Thus, we find that molecularly distinct subpopulations of M1 ipRGCs, which are morphologically and electrophysiologically similar, innervate different brain regions to execute specific light-induced functions.

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References

  1. 1.

    , & Phototransduction by retinal ganglion cells that set the circadian clock. Science 295, 1070–1073 (2002)

  2. 2.

    et al. Melanopsin-expressing retinal ganglion-cell photoreceptors: cellular diversity and role in pattern vision. Neuron 67, 49–60 (2010)

  3. 3.

    , , & A broad role for melanopsin in nonvisual photoreception. J. Neurosci. 23, 7093–7106 (2003)

  4. 4.

    & Melanopsin containing retinal ganglion cells are light responsive from birth. Neuroreport 15, 2317–2320 (2004)

  5. 5.

    , , , & Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science 295, 1065–1070 (2002)

  6. 6.

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

  7. 7.

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

  8. 8.

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

  9. 9.

    , & Photoreceptive net in the mammalian retina. Nature 415, 493 (2002)

  10. 10.

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

  11. 11.

    et al. Physiologic diversity and development of intrinsically photosensitive retinal ganglion cells. Neuron 48, 987–999 (2005)

  12. 12.

    et al. Melanopsin cells are the principal conduits for rod-cone input to non-image-forming vision. Nature 453, 102–105 (2008)

  13. 13.

    et al. Inducible ablation of melanopsin-expressing retinal ganglion cells reveals their central role in non-image forming visual responses. PLoS ONE 3, e2451 (2008)

  14. 14.

    , & Intrinsic and extrinsic light responses in melanopsin-expressing ganglion cells during mouse development. J. Neurophysiol. 100, 371–384 (2008)

  15. 15.

    , , & Synaptic influences on rat ganglion-cell photoreceptors. J. Physiol. (Lond.) 582, 279–296 (2007)

  16. 16.

    & Impaired masking responses to light in melanopsin-knockout mice. Chronobiol. Int. 20, 989–999 (2003)

  17. 17.

    et al. Melanopsin contributions to irradiance coding in the thalamo-cortical visual system. PLoS Biol. 8, e1000558 (2010)

  18. 18.

    , & Morphology and mosaics of melanopsin-expressing retinal ganglion cell types in mice. J. Comp. Neurol. 518, 2405–2422 (2010)

  19. 19.

    et al. Central projections of melanopsin-expressing retinal ganglion cells in the mouse. J. Comp. Neurol. 497, 326–349 (2006)

  20. 20.

    , & Two types of melanopsin retinal ganglion cell differentially innervate the hypothalamic suprachiasmatic nucleus and the olivary pretectal nucleus. Eur. J. Neurosci. 27, 1763–1770 (2008)

  21. 21.

    , , , & Distinct roles of transcription factors Brn3a and Brn3b in controlling the development, morphology, and function of retinal ganglion cells. Neuron 61, 852–864 (2009)

  22. 22.

    et al. New mouse lines for the analysis of neuronal morphology using CreER(T)/loxP-directed sparse labeling. PLoS ONE 4, e7859 (2009)

  23. 23.

    & Functional and morphological differences among intrinsically photosensitive retinal ganglion cells. J. Neurosci. 29, 476–482 (2009)

  24. 24.

    et al. Ganglion cells are required for normal progenitor- cell proliferation but not cell-fate determination or patterning in the developing mouse retina. Curr. Biol. 15, 525–530 (2005)

  25. 25.

    , , & POU domain factor Brn-3b is essential for retinal ganglion cell differentiation and survival but not for initial cell fate specification. Dev. Biol. 210, 469–480 (1999)

  26. 26.

    et al. Z/AP, a double reporter for Cre-mediated recombination. Dev. Biol. 208, 281–292 (1999)

  27. 27.

    Parallel processing in the mammalian retina. Nature Rev. Neurosci. 5, 747–757 (2004)

  28. 28.

    , & A noninvasive genetic/pharmacologic strategy for visualizing cell morphology and clonal relationships in the mouse. J. Neurosci. 23, 2314–2322 (2003)

Download references

Acknowledgements

We thank J. Nathans for providing several animal lines (Brn3bCKOAP, R26IAP and Z/AP) that were crucial for the completion of this study. We thank J. L. Ecker, who created the inducible cre line (Opn4CreERT2) we used in this study. We thank Z. Yang in D. Zack’s laboratory for providing the Brn3bZ-dta mouse line, which was generously provided by the original laboratory that created this line: W. Klein. We also thank R. Kuruvilla, H. Zhao, M. Halpern, A. P. Sampath and T. Schmidt for their careful reading of the manuscript and helpful suggestions and the Johns Hopkins University Mouse Tri-Lab for support. This work was supported by the National Institutes of Health grant GM076430 (S.H.), the David and Lucile Packard Foundation (S.H.), and the Alfred P. Sloan Foundation (S.H.).

Author information

Affiliations

  1. Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218, USA

    • S.-K. Chen
    •  & S. Hattar
  2. Retinal Circuit Development & Genetics Unit, N-NRL/NEI/NIH, Bethesda, Maryland 20892, USA

    • T. C. Badea
  3. Department of Neuroscience, Johns Hopkins University-School of Medicine, Baltimore, Maryland 21218, USA

    • S. Hattar

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Contributions

S.-K.C., T.C.B. and S.H. performed all experiments and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to T. C. Badea or S. Hattar.

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    Supplementary Information

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DOI

https://doi.org/10.1038/nature10206

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