Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2.
Cryptochromes regulate the circadian clock in animals and plants. Humans and 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 intrinsic period 1 hr longer than normal. In this study, Cry1(-/-) and Cry1(-/-)Cry2(-/-) mice were generated and their circadian clocks were analyzed at behavioral and molecular levels. Behaviorally, the Cry1(-/-) mice had a circadian period 1 hr shorter than wild type and the Cry1(-/-)Cry2(-/-) mice were arrhythmic in constant darkness (DD). Biochemically, acute light induction of mPer1 mRNA in the SCN was blunted in Cry1(-/-) and abolished in Cry1(-/-)Cry2(-/-) mice. In contrast, the acute light induction of mPer2 in the SCN was intact in Cry1(-/-) and Cry1(-/-)Cry2(-/-) animals. Importantly, in double mutants, mPer1 expression was constitutively elevated and no rhythmicity 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 are required for the normal expression of circadian behavioral rhythms, as well as circadian rhythms of mPer1 and mPer2 in the SCN. The differential regulation of mPer1 and mPer2 by light in Cry double mutants reveals a surprising complexity in the role of cryptochromes in mammals.
Vitaterna
M H
MH
Department of Neurobiology, Northwestern University, Evanston, IL 60208, USA.
Selby
C P
CP
Todo
T
T
Niwa
H
H
Thompson
C
C
Fruechte
E M
EM
Hitomi
K
K
Thresher
R J
RJ
Ishikawa
T
T
Miyazaki
J
J
Takahashi
J S
JS
Sancar
A
A
D000818:Animals; D018797:Cell Cycle Proteins; D002940:Circadian Rhythm / Q000235:genetics*; D056931:Cryptochromes; D029721:Drosophila Proteins; D005136:Eye Proteins; D005420:Flavoproteins / Q000502:physiology*; D005786:Gene Expression Regulation; D005838:Genotype; D051379:Mice; D008954:Models, Biological; D008957:Models, Genetic; D016296:Mutagenesis; D009687:Nuclear Proteins / Q000235:genetics*; D056950:Period Circadian Proteins; D017956:Photoreceptor Cells, Invertebrate; D043562:Receptors, G-Protein-Coupled; D015398:Signal Transduction; D014157:Transcription Factors
C538963:CRY1 protein, human; C538966:CRY2 protein, human; D018797:Cell Cycle Proteins; C538964:Cry1 protein, mouse; C538967:Cry2 protein, mouse; D056931:Cryptochromes; D029721:Drosophila Proteins; D005136:Eye Proteins; D005420:Flavoproteins; D009687:Nuclear Proteins; C539022:PER1 protein, human; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; C119828:cry protein, Drosophila