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

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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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.

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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.).

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

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

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The authors declare no competing financial interests.

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Chen, SK., Badea, T. & Hattar, S. Photoentrainment and pupillary light reflex are mediated by distinct populations of ipRGCs. Nature 476, 92–95 (2011). https://doi.org/10.1038/nature10206

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