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

[1]  Gregor Eichele,et al.  Studying gene expression on tissue sections using in situ hybridization. , 1997 .

[2]  R. Krumlauf,et al.  Hoxb-4 (Hox-2.6) mutant mice show homeotic transformation of a cervical vertebra and defects in the closure of the sternal rudiments , 1993, Cell.

[3]  G. Eichele,et al.  The mPer2 gene encodes a functional component of the mammalian circadian clock , 1999, Nature.

[4]  Steven M. Reppert,et al.  Posttranslational Mechanisms Regulate the Mammalian Circadian Clock , 2001, Cell.

[5]  U. Albrecht.  Functional Genomics of Sleep and Circadian Rhythm Invited Review: Regulation of mammalian circadian clock genes , 2002 .

[6]  R. Fehon,et al.  A systematic screen for dominant second-site modifiers of Merlin/NF2 phenotypes reveals an interaction with blistered/DSRF and scribbler. , 2001, Genetics.

[7]  Gregor Eichele,et al.  Nonredundant Roles of the mPer1 and mPer2 Genes in the Mammalian Circadian Clock , 2001, Cell.

[8]  J. Kimble,et al.  Identification of genes that interact with glp-1, a gene required for inductive cell interactions in Caenorhabditis elegans. , 1989, Development.

[9]  F. Tamanini,et al.  Nucleocytoplasmic shuttling and mCRY‐dependent inhibition of ubiquitylation of the mPER2 clock protein , 2002, The EMBO journal.

[10]  F. Tamanini,et al.  Dimerization and nuclear entry of mPER proteins in mammalian cells. , 2000, Genes & development.

[11]  Rae Silver,et al.  Expression of Period Genes: Rhythmic and Nonrhythmic Compartments of the Suprachiasmatic Nucleus Pacemaker , 2001, The Journal of Neuroscience.

[12]  M. Therrien,et al.  KSR is a scaffold required for activation of the ERK/MAPK module. , 2002, Genes & development.

[13]  Gregor Eichele,et al.  RIGUI, a Putative Mammalian Ortholog of the Drosophila period Gene , 1997, Cell.

[14]  John B. Hogenesch,et al.  Mop3 Is an Essential Component of the Master Circadian Pacemaker in Mammals , 2000, Cell.

[15]  E. Maywood,et al.  Analysis of Clock Proteins in Mouse SCN Demonstrates Phylogenetic Divergence of the Circadian Clockwork and Resetting Mechanisms , 2000, Neuron.

[16]  D. Virshup,et al.  Nuclear Export of Mammalian PERIOD Proteins* , 2001, The Journal of Biological Chemistry.

[17]  C. Holm,et al.  Dominant mutations in three different subunits of replication factor C suppress replication defects in yeast PCNA mutants. , 1999, Genetics.

[18]  U. Albrecht,et al.  The circadian clock and behavior , 2001, Behavioural Brain Research.

[19]  Steven M. Reppert,et al.  Differential Functions of mPer1, mPer2, and mPer3 in the SCN Circadian Clock , 2001, Neuron.

[20]  Masaaki Ikeda,et al.  Interactivating feedback loops within the mammalian clock: BMAL1 is negatively autoregulated and upregulated by CRY1, CRY2, and PER2. , 2002, Biochemical and biophysical research communications.

[21]  L. Glass,et al.  From Clocks to Chaos: The Rhythms of Life , 1988 .

[22]  Gregor Eichele,et al.  A Differential Response of Two Putative Mammalian Circadian Regulators, mper1 and mper2, to Light , 1997, Cell.

[23]  Steven M Reppert,et al.  mCRY1 and mCRY2 Are Essential Components of the Negative Limb of the Circadian Clock Feedback Loop , 1999, Cell.

[24]  N. Grandin,et al.  Hsp90 levels affect telomere length in yeast , 2001, Molecular Genetics and Genomics.

[25]  D. P. King,et al.  Molecular genetics of circadian rhythms in mammals. , 2000, Annual review of neuroscience.

[26]  J. Miyazaki,et al.  Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[27]  D. V. Leenen,et al.  Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms , 1999, Nature.

[28]  C. Weitz,et al.  Light-independent role of CRY1 and CRY2 in the mammalian circadian clock. , 1999, Science.

[29]  Yoshiyuki Sakaki,et al.  Circadian oscillation of a mammalian homologue of the Drosophila period gene , 1997, Nature.

[30]  K. Miyazaki,et al.  Nuclear Entry Mechanism of Rat PER2 (rPER2): Role of rPER2 in Nuclear Localization of CRY Protein , 2001, Molecular and Cellular Biology.

[31]  Michael C. Mackey,et al.  From Clocks to Chaos , 1988 .

[32]  William J. Schwartz,et al.  Morning and evening circadian oscillations in the suprachiasmatic nucleus in vitro , 2000, Nature Neuroscience.

[33]  A. Goldbeter,et al.  Limit Cycle Models for Circadian Rhythms Based on Transcriptional Regulation in Drosophila and Neurospora , 1999, Journal of biological rhythms.

[34]  K Kume,et al.  Interacting molecular loops in the mammalian circadian clock. , 2000, Science.