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. 2000 Dec 19;97(26):14697-702.
doi: 10.1073/pnas.260498597.

Functional redundancy of cryptochromes and classical photoreceptors for nonvisual ocular photoreception in mice

C P Selby  1 , C Thompson, T M Schmitz, R N Van Gelder, A Sancar
Affiliations

Functional redundancy of cryptochromes and classical photoreceptors for nonvisual ocular photoreception in mice

C P Selby et al. Proc Natl Acad Sci U S A. .

Abstract

The daily light-dark (LD) cycle exerts a powerful influence on the temporal organization of behavior and physiology. Much of this influence is preserved in behaviorally blind retinally degenerate mice; the photoreceptors underlying this nonvisual phototransduction are unknown. The mammalian eye contains at least two classes of photoactive pigments, the vitamin A-based opsins and the vitamin B(2)-based cryptochromes. To genetically define the roles of these pigments in light modulation of behavior, we generated rd/rd;mCry1(-)/mCry1(-);mCry2(-)/mCry2(-) mutant mice lacking rods and most cones as well as both cryptochrome proteins. The response of the mutant mouse to photic input was analyzed at both behavioral and molecular levels. Behaviorally, mice lacking either classical photoreceptors or cryptochromes exhibited strongly rhythmic locomotor responses to 10 and 100 lux daily LD 12 h/12-h cycles; however, triple mutant mice carrying both cryptochrome and retinal degenerate mutations were nearly arrhythmic under both LD cycles and in constant darkness. At the molecular level, the light induction of c-fos transcription in the suprachiasmatic nucleus was markedly reduced in the triple mutant mouse compared with either rd/rd or cryptochrome mutant mice. These data indicate that classical opsins and cryptochromes serve functionally redundant roles in the transduction of light information to behavioral modulation and suggest a pleomorphic role for cryptochromes in both photoreception and central clock mechanism.

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Figures

Figure 1
Figure 1
Genotyping of Cry1, Cry2, and rd alleles by PCR. Results are shown for a wild type and a triple mutant and were obtained by using PCR primers described previously (38, 44). K, knockout; W, wild type.
Figure 2
Figure 2
Histology of wild-type and mutant mouse retinas. (A) Wild-type (C57BL/6). (B) mCry1−/mCry1−; mCry2−/mCry2−. (C) rd/rd. (D) rd/rd; mCry1−/mCry1−; mCry2−/mCry2−. GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer; OS, outer segment; Chor, choroid. Note the nearly complete histologic absence of ONL and OS in C and D.
Figure 3
Figure 3
Behavioral analysis of mutant mice. Representative raster plotted actograms (Left) and corresponding periodograms (Right) for the LD12:12 portions of experiments rd/rd; mCry1−/mCry1−; mCry2−/mCry2− (A), mCry1−/mCry1−; mCry2−/mCry2− (B), and rd/rd (C) mice. Lighting condition is summarized by the shaded bar to the right of the actogram. Gray represents 10-lux lighting, white represents 100 lux, and black represents total darkness. The significance line for periodograms is at P < 0.001. (D–F) Distribution of daily activity in LD12:12. Hourly fractions of accumulated daily wheel turns were calculated for rd/rd; mCry1−/mCry1−; mCry2−/mCry2− (diamonds), mCry1−/mCry1−; mCry2−/mCry2− (squares), and rd/rd (triangles) for all LD12:12 lighting conditions (D), 100 lux (E), and 10 lux (F). Data are represented as mean ± standard error: rd/rd; mCry1−/mCry1−; mCry2−/mCry2−, n = 5, total LD12:12 animal-recording days = 54; mCry1−/mCry1−; mCry2−/mCry2−, n = 2, total LD12:12 animal-recording days = 22; rd/rd, n = 2, total LD12:12 animal-recording days = 26.
Figure 4
Figure 4
Roles of cryptochromes and classic opsins in the photoinduction of c-fos in SCN. (A) Representative slices exhibiting the strongest signal at each light dose in the SCN are shown for each of the four genotypes. (B) Dose–response plot of c-fos induction in the SCN of wild-type and mutant mice. Levels of c-fos are expressed relative to the wild type at the highest dose used (79,000 μmol/m2), which is taken as 100%. The bars indicate standard deviations. The number of animals used for the three lower doses was n = 3, and for the highest dose n = 7–9. Statistical analyses by using a one-tailed paired t test showed that induction in the triple mutant was significantly different (P < 0.05) from wild type at all doses tested.
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