Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

PNAS 103 (27): 10432-10437

Copyright © 2006 by the National Academy of Sciences.

From the Cover


BIOLOGICAL SCIENCES / NEUROSCIENCE

Nonvisual light responses in the Rpe65 knockout mouse: Rod loss restores sensitivity to the melanopsin system

Susan E. Doyle*,{dagger}, Ana Maria Castrucci*,{ddagger}, Maureen McCall§, Ignacio Provencio*, and Michael Menaker*

*Department of Biology, University of Virginia, Charlottesville, VA 22904; {ddagger}Graduate Program in Physiology, Institute of Bioscience, University of São Paulo, 05508-900, São Paulo, Brazil; and §Departments of Ophthalmology and Visual Sciences and Psychological and Brain Sciences, University of Louisville, Louisville, KY 40292

Edited by Joseph S. Takahashi, Northwestern University, Evanston, IL, and approved May 8, 2006

Received for publication February 6, 2006.

Abstract: Intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing the photopigment melanopsin (OPN4), together with rods and cones, provide light information driving nonvisual light responses. We examined nonvisual photoreception in mice lacking RPE65, a protein that is required for regeneration of visual chromophore in rods and cones. Although Rpe65 knockouts retain a small degree of rod function, we show here that circadian phase shifting responses in Rpe65–/– mice are attenuated far beyond what has been reported for rodless/coneless mice. Furthermore, the number of melanopsin-immunoreactive perikarya and the extent of dendritic arborizations were decreased in Rpe65 knockout mice compared with controls. To assess the nature of the photoreceptive defect in Rpe65 null mice, we eliminated either rods or melanopsin from Rpe65–/– retinas by generating (i) Rpe65–/– mice carrying a transgene (rdta) that results in selective elimination of rods and (ii) double knockout Rpe65–/–;Opn4–/– mice. Surprisingly, rod loss in Rpe65 knockout mice resulted in restoration of circadian photosensitivity. Normal photoentrainment was lost in Rpe65–/–;Opn4–/– mice, and, instead, a diurnal phenotype was observed. Our findings demonstrate that RPE65 is not required for ipRGC function but reveal the existence of a mechanism whereby rods may influence the function of ipRGCs.

Key Words: circadian • entrainment • chromophore • isomerohydrolase


Author contributions: S.E.D., A.M.C., M. McCall, I.P., and M. Menaker designed research; S.E.D. and A.M.C. performed research; M. McCall and I.P. contributed new reagents/analytic tools; S.E.D. and A.M.C. analyzed data; and S.E.D. wrote the paper.

Conflict of interest statement: No conflicts declared.

This paper was submitted directly (Track II) to the PNAS office.

See Commentary on page 10153.

{dagger}To whom correspondence should be addressed at: Department of Biology, University of Virginia, Gilmer Hall, P.O. Box 403028, Charlottesville, VA 22904. E-mail: sed5c{at}virginia.edu

© 2006 by The National Academy of Sciences of the USA


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Chromatic Pupillometry Dissects Function of the Three Different Light-Sensitive Retinal Cell Populations in RPE65 Deficiency.
B. Lorenz, E. Strohmayr, S. Zahn, C. Friedburg, M. Kramer, M. Preising, and K. Stieger (2012)
Invest. Ophthalmol. Vis. Sci. 53, 5641-5652
   Abstract »    Full Text »    PDF »
Melanopsin and Mechanisms of Non-visual Ocular Photoreception.
T. Sexton, E. Buhr, and R. N. Van Gelder (2012)
J. Biol. Chem. 287, 1649-1656
   Abstract »    Full Text »    PDF »
Early Onset and Differential Temporospatial Expression of Melanopsin Isoforms in the Developing Chicken Retina.
D. M. Verra, M. A. Contin, D. Hicks, and M. E. Guido (2011)
Invest. Ophthalmol. Vis. Sci. 52, 5111-5120
   Abstract »    Full Text »    PDF »
Intrinsically Photosensitive Retinal Ganglion Cells.
M. T. H. Do and K.-W. Yau (2010)
Physiol Rev 90, 1547-1581
   Abstract »    Full Text »    PDF »
Quantitative Mapping of Ion Channel Regulation by Visual Cycle Activity in Rodent Photoreceptors In Vivo.
B. A. Berkowitz, R. Roberts, D. A. Oleske, M. Chang, S. Schafer, D. Bissig, and M. Gradianu (2009)
Invest. Ophthalmol. Vis. Sci. 50, 1880-1885
   Abstract »    Full Text »    PDF »
Retinal pathways influence temporal niche.
S. E. Doyle, T. Yoshikawa, H. Hillson, and M. Menaker (2008)
PNAS 105, 13133-13138
   Abstract »    Full Text »    PDF »
Retina-clock relations dictate nocturnal to diurnal behaviors.
D. S. McNeill, C. M. Altimus, and S. Hattar (2008)
PNAS 105, 12645-12646
   Full Text »    PDF »
Divergent Phenotypes of Vision and Accessory Visual Function in Mice with Visual Cycle Dysfunction (Rpe65rd12) or Retinal Degeneration (rd/rd).
S. Thompson, R. F. Mullins, A. R. Philp, E. M. Stone, and N. Mrosovsky (2008)
Invest. Ophthalmol. Vis. Sci. 49, 2737-2742
   Abstract »    Full Text »    PDF »
Light-Evoked Calcium Responses of Isolated Melanopsin-Expressing Retinal Ganglion Cells.
A. T. E. Hartwick, J. R. Bramley, J. Yu, K. T. Stevens, C. N. Allen, W. H. Baldridge, P. J. Sollars, and G. E. Pickard (2007)
J. Neurosci. 27, 13468-13480
   Abstract »    Full Text »    PDF »
Melanopsin-Dependent Nonvisual Responses: Evidence for Photopigment Bistability In Vivo.
L. S. Mure, C. Rieux, S. Hattar, and H. M. Cooper (2007)
J Biol Rhythms 22, 411-424
   Abstract »    PDF »
Melanopsin-Dependent Persistence and Photopotentiation of Murine Pupillary Light Responses.
Y. Zhu, D. C. Tu, D. Denner, T. Shane, C. M. Fitzgerald, and R. N. Van Gelder (2007)
Invest. Ophthalmol. Vis. Sci. 48, 1268-1275
   Abstract »    Full Text »    PDF »
Entrainment of the Human Circadian Clock.
T. Roenneberg and M. Merrow (2007)
Cold Spring Harb Symp Quant Biol 72, 293-299
   Abstract »    PDF »
Circadian Photoreception in Vertebrates.
S. Doyle and M. Menaker (2007)
Cold Spring Harb Symp Quant Biol 72, 499-508
   Abstract »    PDF »
Multiple Photoreceptors Contribute to Nonimage-forming Visual Functions Predominantly through Melanopsin-containing Retinal Ganglion Cells.
A.D. Guler, C.M. Altimus, J.L. Ecker, and S. Hattar (2007)
Cold Spring Harb Symp Quant Biol 72, 509-515
   Abstract »    PDF »
Chromophore regeneration: Melanopsin does its own thing.
R. J. Lucas (2006)
PNAS 103, 10153-10154
   Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882