Disruption of mCry2 restores circadian rhythmicity in mPer2 mutant mice.
Many biochemical, physiological, and behavioral processes display daily rhythms generated by an internal timekeeping mechanism referred to as the circadian clock. The core oscillator driving this clock is located in the ventral part of the hypothalamus, the so called suprachiasmatic nuclei (SCN). At the molecular level, this oscillator is thought to be composed of interlocking autoregulatory feedback loops involving a set of clock genes. Among the components driving the mammalian circadian clock are the Period 1 and 2 (mPer1 and mPer2) and Cryptochrome 1 and 2 (mCry1 and mCry2) genes. A mutation in the mPer2 gene leads to a gradual loss of circadian rhythmicity in mice kept in constant darkness (DD). Here we show that inactivation of the mCry2 gene in mPer2 mutant mice restores circadian rhythmicity and normal clock gene expression patterns. Thus, mCry2 can act as a nonallelic suppressor of mPer2, which points to direct or indirect interactions of PER2 and CRY2 proteins. In marked contrast, inactivation of mCry1 in mPer2 mutant mice does not restore circadian rhythmicity but instead results in complete behavioral arrhythmicity in DD, indicating different effects of mCry1 and mCry2 in the clock mechanism
Oster
Henrik
H
Max Planck Institute for Experimental Endocrinology, 30625 Hannover, Germany.
Yasui
Akira
A
van der Horst
Gijsbertus T J
GT
Albrecht
Urs
U
D000818:Animals; D001683:Biological Clocks / Q000502:physiology*; D015152:Blotting, Northern; D018797:Cell Cycle Proteins; D002940:Circadian Rhythm / Q000502:physiology*; D056931:Cryptochromes; D029721:Drosophila Proteins; D005136:Eye Proteins; D005420:Flavoproteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D005799:Genes, Dominant / Q000502:physiology; D017403:In Situ Hybridization; D007668:Kidney / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D056950:Period Circadian Proteins; D017956:Photoreceptor Cells, Invertebrate; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D013493:Suprachiasmatic Nucleus / Q000378:metabolism; D014157:Transcription Factors
D018797:Cell Cycle Proteins; C538967:Cry2 protein, mouse; D056931:Cryptochromes; D029721:Drosophila Proteins; D005136:Eye Proteins; D005420:Flavoproteins; D009687:Nuclear Proteins; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; C119828:cry protein, Drosophila