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

Martha Hotz Vitaterna, Christopher P. Selby, Takeshi Todo, Hitoshi Niwa, Carol Thompson, Ethan M. Fruechte, Kenichi Hitomi, Randy J. Thresher, Tomoko Ishikawa, Junichi Miyazaki, Joseph S. Takahashi, Aziz Sancar

Research output: Contribution to journalArticle

471 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)12114-12119
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number21
DOIs
StatePublished - Oct 12 1999

Fingerprint

Cryptochromes
Periodicity
Suprachiasmatic Nucleus
Light
Genes
Circadian Clocks
Circadian Rhythm
Darkness
Mammals
Messenger RNA

Keywords

  • Gene targeting
  • Photoreceptor
  • Suprachiasmatic nucleus

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2. / Vitaterna, Martha Hotz; Selby, Christopher P.; Todo, Takeshi; Niwa, Hitoshi; Thompson, Carol; Fruechte, Ethan M.; Hitomi, Kenichi; Thresher, Randy J.; Ishikawa, Tomoko; Miyazaki, Junichi; Takahashi, Joseph S.; Sancar, Aziz.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 21, 12.10.1999, p. 12114-12119.

Research output: Contribution to journalArticle

Vitaterna, MH, Selby, CP, Todo, T, Niwa, H, Thompson, C, Fruechte, EM, Hitomi, K, Thresher, RJ, Ishikawa, T, Miyazaki, J, Takahashi, JS & Sancar, A 1999, 'Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2', Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 21, pp. 12114-12119. https://doi.org/10.1073/pnas.96.21.12114
Vitaterna, Martha Hotz ; Selby, Christopher P. ; Todo, Takeshi ; Niwa, Hitoshi ; Thompson, Carol ; Fruechte, Ethan M. ; Hitomi, Kenichi ; Thresher, Randy J. ; Ishikawa, Tomoko ; Miyazaki, Junichi ; Takahashi, Joseph S. ; Sancar, Aziz. / Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2. In: Proceedings of the National Academy of Sciences of the United States of America. 1999 ; Vol. 96, No. 21. pp. 12114-12119.
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abstract = "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.",
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AU - Vitaterna, Martha Hotz

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AU - Thompson, Carol

AU - Fruechte, Ethan M.

AU - Hitomi, Kenichi

AU - Thresher, Randy J.

AU - Ishikawa, Tomoko

AU - Miyazaki, Junichi

AU - Takahashi, Joseph S.

AU - Sancar, Aziz

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