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.
Nonvisual light responses in the Rpe65 knockout mouse: Rod loss restores sensitivity to the melanopsin system
Susan E. Doyle*,,
Ana Maria Castrucci*,,
Maureen McCall,
Ignacio Provencio*, and
Michael Menaker*
*Department of Biology, University of Virginia, Charlottesville, VA 22904; 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 withrods and cones, provide light information driving nonvisuallight responses. We examined nonvisual photoreception in micelacking RPE65, a protein that is required for regeneration ofvisual chromophore in rods and cones. Although Rpe65 knockoutsretain a small degree of rod function, we show here that circadianphase shifting responses in Rpe65–/– mice are attenuatedfar beyond what has been reported for rodless/coneless mice.Furthermore, the number of melanopsin-immunoreactive perikaryaand the extent of dendritic arborizations were decreased inRpe65 knockout mice compared with controls. To assess the natureof the photoreceptive defect in Rpe65 null mice, we eliminatedeither rods or melanopsin from Rpe65–/– retinasby 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 restorationof circadian photosensitivity. Normal photoentrainment was lostin Rpe65–/–;Opn4–/– mice, and, instead,a diurnal phenotype was observed. Our findings demonstrate thatRPE65 is not required for ipRGC function but reveal the existenceof a mechanism whereby rods may influence the function of ipRGCs.
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.
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
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 »
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.
,
Ana Maria Castrucci*,
,
Maureen McCall
,
Ignacio Provencio*, and
Michael Menaker*
To whom correspondence should be addressed at: Department of Biology, University of Virginia, Gilmer Hall, P.O. Box 403028, Charlottesville, VA 22904. E-mail: 
