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

The daily light-dark (LD) cycle exerts a powerful influence on the temporal organization of behavior and physiology. Much of this influence is preserv ed in behaviorally blind retinally degenerate mice; the photoreceptors unde rlying this nonvisual phototransduction are unknown. The mammalian eye cont ains at least two classes of photoactive pigments, the vitamin A-based opsi ns and the vitamin B-2-based cryptochromes. To genetically define the roles of these pigments in light modulation of behavior, we generated rd/rd;mCry 1(-)/mCry1(-);mCry2(-)/mCry2(-) mutant mice lacking rods and most cones as well as both cryptochrome proteins. The response of the mutant mouse to pho tic input was analyzed at both behavioral and molecular levels. behaviorall y, 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 con stant darkness. At the molecular level, the light induction of c-fos transc ription in the suprachiasmatic nucleus was markedly reduced in the triple m utant mouse compared with either rd/rd or cryptochrome mutant mice. These d ata indicate that classical opsins and cryptochromes serve functionally red undant roles in the transduction of light information to behavioral modulat ion and suggest a pleomorphic role for cryptochromes in both photoreception and central clock mechanism.