Differential Functions of mPer1, mPer2, and mPer3 in the SCN Circadian Clock

The role of mPer1 and mPer2 in regulating circadian rhythms was assessed by disrupting these genes. Mice homozygous for the targeted allele of either mPer1 or mPer2 had severely disrupted locomotor activity rhythms during extended exposure to constant darkness. Clock gene RNA rhythms were blunted in the suprachiasmatic nucleus of mPer2 mutant mice, but not of mPER1-deficient mice. Peak mPER and mCRY1 protein levels were reduced in both lines. Behavioral rhythms of mPer1/mPer3 and mPer2/mPer3 double-mutant mice resembled rhythms of mice with disruption of mPer1 or mPer2 alone, respectively, confirming the placement of mPer3 outside the core circadian clockwork. In contrast, mPer1/mPer2 double-mutant mice were immediately arrhythmic. Thus, mPER1 influences rhythmicity primarily through interaction with other clock proteins, while mPER2 positively regulates rhythmic gene expression, and there is partial compensation between products of these two genes.

[1]  Minoru Tanaka,et al.  Positional Cloning of the Mouse Circadian Clock Gene , 1997, Cell.

[2]  E. Eide,et al.  Nuclear Entry of the Circadian Regulator mPER1 Is Controlled by Mammalian Casein Kinase I ɛ , 2000, Molecular and Cellular Biology.

[3]  D. P. King,et al.  Role of the CLOCK protein in the mammalian circadian mechanism. , 1998, Science.

[4]  Lily Yan,et al.  Light-Induced Resetting of a Mammalian Circadian Clock Is Associated with Rapid Induction of the mPer1 Transcript , 1997, Cell.

[5]  D. S. Hsu,et al.  Role of mouse cryptochrome blue-light photoreceptor in circadian photoresponses. , 1998, Science.

[6]  Steven M Reppert,et al.  Three period Homologs in Mammals: Differential Light Responses in the Suprachiasmatic Circadian Clock and Oscillating Transcripts Outside of Brain , 1998, Neuron.

[7]  Mark J. Zylka,et al.  Two period Homologs: Circadian Expression and Photic Regulation in the Suprachiasmatic Nuclei , 1997, Neuron.

[8]  Joel D Levine,et al.  Molecular Analysis of Mammalian Timeless , 1998, Neuron.

[9]  P. Hardin,et al.  Interlocked feedback loops within the Drosophila circadian oscillator. , 1999, Science.

[10]  Christopher R. Jones,et al.  An hPer2 Phosphorylation Site Mutation in Familial Advanced Sleep Phase Syndrome , 2001, Science.

[11]  S. Reppert,et al.  Molecular analysis of mammalian circadian rhythms. , 2001, Annual review of physiology.

[12]  N. Mrosovsky,et al.  Rapid down-regulation of mammalian period genes during behavioral resetting of the circadian clock. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Y Sakaki,et al.  The human and mouse Period1 genes: five well-conserved E-boxes additively contribute to the enhancement of mPer1 transcription. , 2000, Genomics.

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

[15]  A Yasui,et al.  Photic induction of mPer1 and mPer2 in cry-deficient mice lacking a biological clock. , 1999, Science.

[16]  E. Maywood,et al.  Differential Regulation of mPER1 and mTIM Proteins in the Mouse Suprachiasmatic Nuclei: New Insights into a Core Clock Mechanism , 1999, The Journal of Neuroscience.

[17]  D. Sidote,et al.  Circadian Regulation of a Drosophila Homolog of the Mammalian Clock Gene: PER and TIM Function as Positive Regulators , 1998, Molecular and Cellular Biology.

[18]  D. P. King,et al.  Mammalian Circadian Autoregulatory Loop A Timeless Ortholog and mPer1 Interact and Negatively Regulate CLOCK-BMAL1-Induced Transcription , 1998, Neuron.

[19]  M. W. Young,et al.  A light‐independent oscillatory gene mPer3 in mouse SCN and OVLT , 1998, The EMBO journal.

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

[21]  J. Takahashi,et al.  Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. , 2000, Science.

[22]  Mark J. Zylka,et al.  A Molecular Mechanism Regulating Rhythmic Output from the Suprachiasmatic Circadian Clock , 1999, Cell.

[23]  J. Dunlap,et al.  Interconnected feedback loops in the Neurospora circadian system. , 2000, Science.

[24]  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.

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

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

[27]  S. Shibata,et al.  Additive effect of mPer1 and mPer2 antisense oligonucleotides on light-induced phase shift , 2001, Neuroreport.

[28]  S. Shibata,et al.  Nonphotic Entrainment by 5-HT1A/7 Receptor Agonists Accompanied by Reduced Per1 and Per2 mRNA Levels in the Suprachiasmatic Nuclei , 2000, The Journal of Neuroscience.

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

[30]  D. Weaver.  The Suprachiasmatic Nucleus: A 25-Year Retrospective , 1998, Journal of biological rhythms.

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

[32]  J. Dunlap.  Molecular Bases for Circadian Clocks , 1999, Cell.

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

[34]  Shigenori Watanabe,et al.  Inhibition of Light- or Glutamate-Induced mPer1Expression Represses the Phase Shifts into the Mouse Circadian Locomotor and Suprachiasmatic Firing Rhythms , 1999, The Journal of Neuroscience.

[35]  D. P. King,et al.  Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. , 1994, Science.

[36]  B. Zheng,et al.  mPer1 and mPer2 Are Essential for Normal Resetting of the Circadian Clock , 2001, Journal of biological rhythms.

[37]  Markus Meister,et al.  Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms , 1995, Neuron.

[38]  O. Khorkova,et al.  Human casein kinase Iδ phosphorylation of human circadian clock proteins period 1 and 2 , 2001, FEBS letters.

[39]  J. Hogenesch,et al.  The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

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

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

[42]  D. Virshup,et al.  Phosphorylation and destabilization of human period I clock protein by human casein kinase Iε , 2000, Neuroreport.

[43]  S. Reppert,et al.  Targeted Disruption of the mPer3 Gene: Subtle Effects on Circadian Clock Function , 2000, Molecular and Cellular Biology.