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circadian rhythms are fluctuations in physiological and behavioral activities that occur over a period of about 24 hours . although these rhythms parallel environmental cycles of light and dark , they are not simply a reaction to environmental fluctuations , but are generated by an endogenous timekeeping mechanism called the circadian clock .
the ability of the clock to persist in the absence of environmental cues provides internal temporal organization so that rhythmic activities can occur at characteristic times during the circadian cycle . in addition , two other clock properties , entrainment ( that is , setting the clock to local time with respect to environmental cycles ) and temperature compensation ( that is , the ability of the clock to run at the same rate at different temperatures ) ensure synchrony with the environment .
the importance of the circadian clock is underscored by its ubiquity ; clocks are present in organisms ranging from prokaryotic and eukaryotic microbes to plants , insects and mammals .
the circadian clock has been conceptualized as a series of three components : an ' entrainment pathway ' that transmits environmental ( usually light ) signals to the timekeeping apparatus ; a timekeeping apparatus , or ' oscillator ' , which operates in the absence of environmental cues and is the core component of the circadian clock ; and ' output pathways ' that are activated at specific times of the circadian cycle by the circadian oscillator .
this framework has enabled us to concentrate on the mechanisms that interconnect these components to form an effective timekeeping system .
naturally , a great deal of effort has been focused on identifying genes that encode pieces of the oscillator - also known as ' clock genes ' .
the increasing volume of genomic and expressed sequence tag ( est ) sequences has rapidly increased the pace of clock gene discovery , particularly in mammals ; and the abundance of newly identified clock genes has given rise to detailed models of the oscillator mechanism .
in contrast , relatively little effort has been put into identifying genes within output pathways , even though these pathways provide the critical links to rhythmic physiology and behavior .
new tools that are now available for expression screening should enable rapid advances in the identification of output genes .
on the basis of studies in cyanobacteria , neurospora , drosophila and mice , the core circadian oscillator mechanism is thought to consist of one or more transcriptional feedback loops . despite this conservation of oscillator mechanisms , oscillator components in cyanobacteria and neurospora
in contrast , oscillator components from drosophila and mice show a high degree of sequence similarity , a property that has fueled recent advances in our understanding of the oscillator . essentially all components of the drosophila and mammalian circadian oscillators have been discovered ( directly or indirectly ) as a result of genetic screens for rhythm mutants . in this review
, i will describe the various clock genes , how they were isolated and how they function within the oscillator ( table 1 , figure 1 ) .
the first clock mutants to be discovered identified the period ( per ) gene from drosophila .
this gene encodes a protein , per , that contains a pas domain ( a protein interaction interface ) .
it feeds back as part of a heterodimer with the timeless ( tim ) protein ( tim ) to inhibit per and tim transcription and activate a gene required for per and tim activation , called drosophila clock ( dclk ) .
this differential effect of per - tim heterodimers on transcription gives rise to high levels of per and tim mrna at dusk and high levels of dclk mrna at dawn .
after many years of searching , pcr - based molecular screens and est searches uncovered three mouse per orthologs ( mper1 , mper2 and mper3 ) .
although all three mper proteins are capable of inhibiting mper1 transcription in cell culture , genetic analysis suggests that mper2 also leads to the activation of bmal1 , a gene required for mper1 activation .
these divergent regulatory functions lead to peaks in mper1 transcription during the day and peaks in bmal1 transcription at night . the protein encoded by tim ,
the second clock gene identified in drosophila , dimerizes with , and stabilizes , phosphorylated per , promotes per localization to the nucleus and is degraded in response to light .
these functions of tim allow for an approximately 6 - 8 hour delay in the accumulation of per protein ( with respect to per mrna ) and entrainment of the oscillator to light .
mammalian tim isologs ( related by sequence ) of human ( htim ) and mouse ( mtim ) have been isolated through est database searches .
although the role of mtim in the mouse oscillator is uncertain , it does not promote nuclear localization of the mpers or mediate entrainment to light as tim does in drosophila .
searching the drosophila genome database has , however , led to the discovery of another tim gene , thus opening up the possibility that mtim is not the true homolog of the drosophila tim clock gene .
the first mammalian clock gene identified as a result of genetic screening for rhythm mutants was mouse clock .
this gene , which was isolated by positional cloning and transgenic bacterial artificial chromosome ( bac ) mutant rescue , encodes a basic - helix - loop - helix - pas ( bhlh - pas ) protein ( clock ) which is required for activating the transcription of other clock genes ( mper1 - 3 , and the genes for mouse cryptochromes 1 and 2 ) and of an output gene ( for vasopressin ) .
clock mediates transcriptional activation as part of a heterodimeric complex with bmal1 - a bhlh - pas protein discovered in a yeast two - hybrid screen for proteins that interact with clock .
although bmal1 mrna levels cycle with a peak early at night and clock mrna levels are constant , the levels of bmal1 and clock proteins have not been characterized .
genetic , dna cross - hybridization and est database screens revealed drosophila homologs of clock and bmal1 , termed dclk and cycle ( cyc ) , respectively . as in mammals ,
this heterodimeric complex also activates tim transcription and inhibits dclk transcription , however , thereby accounting for the antiphase cycling of these transcripts .
in contrast to the situation in mammals , dclk mrna cycles with a peak at dawn and cyc mrna levels are constant . the dclk and cyc protein levels parallel
dclk and cyc mrna levels : dclk peaks during early day and cyc does not vary .
perhaps the only mammalian clock genes that were not discovered ( directly or indirectly ) by genetic screening are the mouse cryptochrome genes , mcry1 and mcry2 .
although these genes were initially thought to encode circadian photoreceptors , on the basis of their similarity to plant blue - light receptor cryptochromes , their protein products ( mcry1 and mcry2 ) in fact function within the oscillator to strongly inhibit transcriptional activation by clock - bmal1 and to mediate mper nuclear localization . as mcry1 and mcry2
are activated by clock - bmal1 heterodimers , high levels of the mcry1 and mcry2 inhibitors at dusk feed back to mediate rhythms in the abundance of mcry1 and mcry2 transcripts which , like mper transcripts , peak during the day . in drosophila , a single cryptochrome ( cry ) gene was identified through pcr - based screening for cry homologs and genetic screening for mutants that alter per - promoter - driven luciferase reporter - gene cycling . unlike its mammalian counterparts ,
drosophila cry is involved in receiving light signals and transmitting these signals to the clock by forming a complex with tim .
in addition to the intricate network of factors involved in transcriptional control , factors that mediate post - transcriptional regulatory events are also required for circadian oscillator function ( figure 1 ) .
one component of the post - transcriptional regulatory mechanism in drosophila is doubletime ( dbt ) , a casein kinase i ( cki ) ortholog that was identified by genetic screening .
dbt phosphorylates , and consequently destabilizes , per , which in turn prevents per from accumulating until it forms a heterodimer with tim .
this post - transcriptional regulation leads to a substantial ( approximately 6 hour ) lag between per mrna and per protein accumulation .
the gene corresponding to the first identified mammalian rhythm mutant , called tau , was recently isolated from hamsters via a groundbreaking positional syntenic cloning approach , and found to be a dbt homolog . like dbt , hamster tau - encoded cki acts to phosphorylate per proteins ( at least mper1 and mper2 in vitro ) .
the defective tau - mutant cki leads to a premature rise in hamster per1 levels , which not only explains the short - period phenotype of tau mutants but also suggests that cki destabilizes hamster per1 .
this explosion of clock gene discovery has also enhanced oscillator analysis in non - mammalian vertebrates such as zebrafish and xenopus
. in zebrafish , homologs to bmal1 ( bmal1 and bmal2 ) , clock and mper3 have been isolated using low - stringency hybridization and degenerate pcr .
homologs of other clock genes ( per and cry ) present in zebrafish est databases and new clock mutants ( g. cahill , personal communication ) should provide a detailed picture of the oscillator in this species .
likewise , the xenopus clock gene was recently described   and should fuel the analysis of the frog oscillator mechanism .
the corresponding genes have been isolated , but they are not similar to any known clock genes and do not appear to be part of the core oscillator mechanism .
analysis of additional plant clock mutants should reveal whether oscillator components in plants bear any resemblance to those in other model systems .
the circadian oscillator mechanisms from flies and mice : models depicting the regulatory interactions within the drosophila and mouse feedback loops .
the ' p ' on per and mper represents phosphorylation due to dbt / ck1. the lightning bolt represents light acting on drosophila cry .
circadian clock genes and their functions in drosophila and mice gene symbols are as described in the text .
the ' ? ' for mper1 - 3 and mtim protein function indicates that the indicated activity is presumed on the basis of the clock function of these proteins .
cyc is the drosophila homolog of mouse bmal1 and dbt is the homolog of mouse ck1 and hamster tau .
significant progress has been made in determining how the circadian oscillator keeps time and maintains synchrony with the environment .
relatively little is known , however , about how the oscillator controls rhythmic events so that they occur at particular times of day .
a key to understanding how the oscillator carries out this temporal program is the identification and analysis of output pathways . as rhythmic transcription
is a prominent feature of the oscillator , mechanisms that regulate rhythmic transcription within the oscillator could also be used to control rhythmic expression within output pathways .
rhythmically expressed output genes have been identified in many organisms . in some organisms , such as cyanobacteria ,
rhythmic expression is the rule rather than the exception . in most organisms , however ,
several output genes , including the transcription factors dbp , tef and icer from mice , have been found fortuitously during careful analysis of gene expression .
other clock - regulated genes ( such as that for vasopressin ) were identified because their protein products were expressed in central clock tissues such as the mammalian suprachiasmatic nucleus , and were needed to produce compounds that affect the clock ( for example the enzyme serotonin n - acetyltransferase , which is required for the production of melatonin ) , or were involved in diurnally regulated processes such as photosynthesis ( for example cab and catalase in plants ) .
this identified two clock - controlled genes ( ccgs ) : ccg-1 and ccg-2 ; ccg-2 was later found to be involved in the development of conidia , which are reproductive structures produced in a circadian fashion .
different subtractive hybridization techniques have also been used to isolate ccgs from drosophila , including 20 drosophila rhythmically expressed genes ( dregs ) , crg-1 , and takeout , and ccgs from plants , including sagrp1 and sagrp2 .
another technique that has been used to identify ccgs is differential display reverse - transcription pcr ( dd rt - pcr ) .
this technique was used to identify several ccgs in xenopus , the vrille gene in drosophila   and a set of 17 ccgs from arabidopsis .
the advent of dna microarray technology should enable researchers to identify a vast number of ccgs via differential screening of cdnas or predicted genes from whole genome sequences .
this volume of ccgs should reveal a multitude of clock output pathways and should provide clues to the identity of the physiological and behavioral phenomena they control .
searches for ccgs have so far focused mainly on rhythmically expressed mrnas . in a few cases ,
however , rhythms in protein abundance are seen in the absence of underlying mrna rhythms , indicating that potent clock - dependent post - transcriptional mechanisms are operating .
examples include luciferase - binding protein ( lbp ) , which contributes to bioluminescence rhythms in dinoflagellates , and white collar 1 ( wc1 ) , which is an integral component of the oscillator in neurospora . as rhythms in protein abundance
are generally not investigated unless the corresponding mrna cycles in abundance or the protein contributes to a rhythmic phenomenon , it is possible that other cycling proteins emanate from non - cycling mrnas . by coupling proteomics
technology and mass spectrometry - based protein sequence analysis , particularly in organisms whose genomes have been sequenced , it will be possible to detect and identify proteins that cycle in abundance .
once a comprehensive collection of clock outputs is available , we will be better able to understand how the biological clock orchestrates the temporal program that governs the coordinate expression of biological rhythms .
the genetic and molecular analysis of circadian timekeeping mechanisms has accelerated as a result of the increasing volume of genomic markers and nucleotide sequence information . completion of whole genome sequences and the use of differential gene expression technology will hasten the discovery of the clock output pathways that control diverse rhythmic phenomena .