Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: Co-expression of melanopsin and Brn3b defines a specific set of ipRGCs.
Figure 2: Genetic ablation of Brn3b-positive ipRGCs does not impair targeting to the SCN.
Figure 3: Opn4 Cre/+ ;Brn3 Z-dta/+ mice show severe deficits in the pupillary light reflex (PLR).
Figure 4: Opn4 Cre/+ ;Brn3b Z-dta/+ mice show normal circadian photoentrainment.

Similar content being viewed by others


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

    Article  CAS  Google Scholar 

  3. Gooley, J. J., Lu, J., Fischer, D. & Saper, C. B. A broad role for melanopsin in nonvisual photoreception. J. Neurosci. 23, 7093–7106 (2003)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. 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 

  6. 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 

  7. 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 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  ADS  Google Scholar 

  13. Hatori, M. 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)

    Article  ADS  Google Scholar 

  14. Schmidt, T. M., Taniguchi, K. & Kofuji, P. Intrinsic and extrinsic light responses in melanopsin-expressing ganglion cells during mouse development. J. Neurophysiol. 100, 371–384 (2008)

    Article  CAS  Google Scholar 

  15. Wong, K. Y., Dunn, F. A., Graham, D. M. & Berson, D. M. Synaptic influences on rat ganglion-cell photoreceptors. J. Physiol. (Lond.) 582, 279–296 (2007)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  18. Berson, D. M., Castrucci, A. M. & Provencio, I. Morphology and mosaics of melanopsin-expressing retinal ganglion cell types in mice. J. Comp. Neurol. 518, 2405–2422 (2010)

    Article  Google Scholar 

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

    Article  Google Scholar 

  20. Baver, S. B., Pickard, G. E. & Sollars, P. J. 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)

    Article  Google Scholar 

  21. Badea, T. C., Cahill, H., Ecker, J., Hattar, S. & Nathans, J. Distinct roles of transcription factors Brn3a and Brn3b in controlling the development, morphology, and function of retinal ganglion cells. Neuron 61, 852–864 (2009)

    Article  CAS  Google Scholar 

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

    Article  ADS  Google Scholar 

  23. Schmidt, T. M. & Kofuji, P. Functional and morphological differences among intrinsically photosensitive retinal ganglion cells. J. Neurosci. 29, 476–482 (2009)

    Article  CAS  Google Scholar 

  24. Mu, X. 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)

    Article  CAS  Google Scholar 

  25. Gan, L., Wang, S. W., Huang, Z. & Klein, W. H. 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)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

Download references


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

Authors and Affiliations



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

Corresponding authors

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

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Text, Supplementary Figures 1-6 with legends, Supplementary Table 1 and additional references. (PDF 5850 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Chen, SK., Badea, T. & Hattar, S. Photoentrainment and pupillary light reflex are mediated by distinct populations of ipRGCs. Nature 476, 92–95 (2011).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing