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PNAS 103 (27): 10432-10437

Copyright © 2006 by the National Academy of Sciences.

From the Cover


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}

© 2006 by The National Academy of Sciences of the USA

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