Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2

Cryptochromes regulate the circadian clock in animals and plants. Humans an d mice have two cryptochrome (Cry) genes. A previous study showed that mice lacking the Cry2 gene had reduced sensitivity to acute light induction of the circadian gene mPer1 in the suprachiasmatic nucleus (SCN) and had an in trinsic period 1 hr longer than normal. In this study, Cry1(-/-) and Cry1(- /-)Cry2(-/-) mice were generated and their circadian docks were analyzed at behavioral and molecular levels. Behaviorally, the Cry1(-/-) mice had a ci rcadian period 1 hr shorter than wild type and the Cry1(-/-)Cry2(-/-) mice were arrhythmic in constant darkness (DD). Biochemically, acute light induc tion of mPer1 mRNA in the SCN was blunted in Cry1(-/-) and abolished in Cry 1(-/-)Cry2(-/-) mice. In contrast, the acute light induction of mPer2 in th e SCN was intact in Cry1(-/-) and Cry1(-/-)Cry2(-/-) animals. Importantly, in double mutants, mPer1 expression was constitutively elevated and no rhyt hmicity was detected in either 12-hr light/12-hr dark or DD, whereas mPer2 expression appeared rhythmic in 12-hr light/12-hr dark, but nonrhythmic in DD with intermediate levels. These results demonstrate that Cry1 and Cry2 a re required for the normal expression of circadian behavioral rhythms, as w ell as circadian rhythms of mPer1 and mPer2 in the SCN. The differential re gulation of mPer1 and mPer2 by light in Cry double mutants reveals a surpri sing complexity in the role of cryptochromes in mammals.