In mammals, circadian control of physiology and behavior is driven by a master pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus. We have used gene expression profiling to identify cycling transcripts in the SCN and in the liver. Our analysis revealed approximately 650 cycling transcripts and showed that the majority of these were specific to either the SCN or the liver. Genetic and genomic analysis suggests that a relatively small number of output genes are directly regulated by core oscillator components. Major processes regulated by the SCN and liver were found to be under circadian regulation. Importantly, rate-limiting steps in these various pathways were key sites of circadian control, highlighting the fundamental role that circadian clocks play in cellular and organismal physiology.
Mice deficient in the circadian transcription factor BMAL1 (brain and muscle ARNT-like protein) have impaired circadian behavior and demonstrate loss of rhythmicity in the expression of target genes. Here we report that Bmal1 −/− mice have reduced lifespans and display various symptoms of premature aging including sarcopenia, cataracts, less subcutaneous fat, organ shrinkage, and others. The early aging phenotype correlates with increased levels of reactive oxygen species in some tissues of the Bmal1 −/− animals. These findings, together with data on CLOCK/BMAL1-dependent control of stress responses, may provide a mechanistic explanation for the early onset of age-related pathologies in the absence of BMAL1.Supplemental material is available at http://www.genesdev.org.Received March 22, 2006; revised version accepted May 9, 2006. BMAL1 (brain and muscle ARNT-like protein, also known as MOP3 or ARNT3) belongs to the family of the basic helix-loop-helix (bHLH)-PAS domain-containing transcription factors. In a complex with another member of this family, CLOCK, BMAL1 regulates expression of genes through E-box elements in their promoters. BMAL1, CLOCK, and some of their transcriptional targets (PERIODs and CRYPTOCHROMEs) are the key components of the molecular oscillator that generates circadian rhythms. These 24-h oscillations in behavior, physiology, and metabolism are thought to ensure adaptation of organisms to the 24-h periodicity of the Earth's rotation (Panda et al. 2002b;Lowrey and Takahashi 2004). Although the master circadian clock is located within the hypothalamic suprachiasmatic nucleus (SCN), the key circadian proteins are expressed in many peripheral tissues, determining circadian periodicity in gene expression and physiology for many organs (Reppert and Weaver 2002). Indeed, microarray data show that up to 10% of genes in different tissues are directly or indirectly regulated by the circadian clock system (Panda et al. 2002a;Storch et al. 2002). At the same time, only a few oscillating genes (most of them encoding components of the molecular clock itself) are common to all organs tested. Since different tissues have characteristic sets of genes with clock-regulated timing and amplitude of expression (Panda et al. 2002a;Storch et al. 2002), it is likely that the circadian clock is involved in control of homeostasis in different organs.Mice with mutations or targeted disruptions of core circadian genes that have been generated during the last decade all show impaired circadian behavior and deregulation of circadian patterns in gene expression (Lowrey and Takahashi 2004). In addition to this universal phenotype, other pathological defects are specific for particular circadian mutants. Thus, Clock mutation results in reduced fertility and complications of pregnancy (Miller et al. 2004), obesity and metabolic syndrome (Turek et al. 2005), and sensitization to cocaine (McClung et al. 2005). Period2 deficiency leads to the enhanced voluntary alcohol consumption and alterations in the glutamatergic syste...
We used positional cloning to identify the circadian Clock gene in mice. Clock is a large transcription unit with 24 exons spanning approximately 100,000 bp of DNA from which transcript classes of 7.5 and approximately 10 kb arise. Clock encodes a novel member of the bHLH-PAS family of transcription factors. In the Clock mutant allele, an A-->T nucleotide transversion in a splice donor site causes exon skipping and deletion of 51 amino acids in the CLOCK protein. Clock is a unique gene with known circadian function and with features predicting DNA binding, protein dimerization, and activation domains. CLOCK represents the second example of a PAS domain-containing clock protein (besides Drosophila PERIOD), which suggests that this motif may define an evolutionarily conserved feature of the circadian clock mechanism.
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