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Nonvisual light responses in the Rpe65 knockout mouse: Rod loss restores sensitivity to the melanopsin system
Susan E. Doyle*,,
Ana Maria Castrucci*,,
Ignacio Provencio*, and
*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.
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.