doi:10.1006/scdb.2001.0253, available online at http://www.idealibrary.com onseminars in CELL & DEVELOPMENTAL BIOLOGY , Vol. 12, 2001: pp. 267–269

Introduction: taking stock of circadian clock complexity

Rodolfo Costa

Circadian clocks are ubiquitous! This terse sentencehas been used frequently in the last few years to meannot only that almost all higher organisms (and somebacteria) exhibit circadian rhythmicity controlled byan endogenous circadian clock,1 but also that manyautonomous oscillators are present in different tissuesor organs.2,3 Clock research also represents one ofthe more productive and faster evolving areas of bi-ology, as evidenced by the extraordinary number ofhigh profile publications that keep coming, thick andfast. This in turn has produced a market for reviewsof molecular chronobiology, yet the ‘half-life’ of thesereviews is significantly affected by this explosive accu-mulation of data and discourages potential authors toundertake this (thankless) task. I am therefore partic-ularly pleased that a number of colleagues have com-mitted themselves to write these contributions for thisissue, which cover the most relevant aspects of circa-dian rhythmicity in different model systems.

Tetsuya Mori and Carl Johnson, review thecircadian clock of the freshwater prokaryoteSynechococcus elongatus (cyanobacteria). A propertyof the circadian rhythmicity in this organism, is thesubstantial independence of the circadian and celldivision timing mechanisms. In addition, the clockprotein KaiC, a member of the bacterial RecA/DnaBfamily, binds ATP through putative nucleotide-binding (P-loop) motifs which are indispensablefor rhythmicity. The authors propose a new modelfor the fundamental mechanisms underlying thecircadian clock in S. elongatus, which suggests that theglobal circadian regulation of gene expression is atleast partially mediated by changes in chromosomalstructure/condensation.

The review of the ascomycete Neurospora crassacircadian system by Martha Merrow, Till Roenneberg,

From the Dipartimento di Biologia, Università di Padova, Via U. Bassi58/B, 35131 Padova, Italy.E-mail: costa@civ.bio.unipd.it

c©2001Academic Press1084–9521/01/040267+ 03/$35.00

Lisa Franchi and Pino Macino, focuses in particularon processes involved in light signal transductionto the clockwork, and on the role that the white-collar complex (WCC) plays in the generation ofself-sustained rhythmicity. Evidence is providedthat suggests the existence of a second circadianmachinery which is independent of the classicalfrequency (frq) transcription/translation loop (the so-called frequency-less oscillator, FLO). A parsimoniousmodel of interaction between the two oscillators,which should account for the complexity of theircircadian phenotypes, is also presented.

Drosophila melanogaster represents the organismfor which we have, arguably, the most completeunderstanding for the molecular basis of thecircadian clock. Unlike the majority of reviews onthis organism which usually focus on a model basedon a rather simple negative feedback loop, JustinBlau discusses a more realistic model, emphasizingboth what is known and what is still obscure. Withinthis context is a critical analysis on the nature of therepressor of the dClock gene, which concludes thatvrille could play this role, followed by a discussion onthe possible multiple roles for doubletime (dbt).

Since 1997, it has become clear that remarkablesimilarities exist between the mechanisms underlyingmammalian and fruitfly clocks.4 They sharehomologous clock genes, although some of theirregulatory relationships have been altered duringthe evolutionary process. In their contribution,Erik Herzog and Gianluca Tosini describe themain features of the mammalian master circadianpacemaker which is localized in the suprachiasmaticnuclei (SCN) of the hypothalamus. They describethe mechanisms responsible for the synchronizationof rhythmicity within the SCN and revise and extend(with experimental support) a 1974 hypothesisproposed by Colin Pittendrigh, on the existencewithin the SCN of two interacting oscillators. Theyalso report on peripheral oscillators which have beenrecently discovered in the mouse lung, liver, kidneyand skeletal muscle. This circadian rhythmicitydamps out when these tissues are ‘isolated’, but is

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sustained when coupled to the SCN master clock invivo. Surprisingly, some of these multiple circadianoscillators can be independently synchronized todifferent environmental and metabolic stimuli.

Laura Roden and Isabelle Carré discuss recent workwith Arabidopsis thaliana, and review the identificationof the first putative components of the plant circadianpacemaker (TOC1, LHY and CCA1) which seem notto share evolutionary similarities to clock genes fromother organisms. Light input to the clock is complex,with at least six different photoreceptors involved.Some of the downstream components of the photo-signal-transduction pathway that regulate the clockhave also been isolated. Circadian photoreceptorsare expressed rhythmically, as are several downstreamsignal transduction components. Nevertheless,the biological function of these ‘zeithnemer’ loopsremain unknown, and no clear patterns of interactionamong the Arabidopsis clock-associated genes (withinthe light input pathway or the oscillator) haveemerged so far.

The remaining two chapters in this volume dealwith fundamental aspects of the organization andfunctioning of a circadian clock in relation to theexternal environmental signals and clock outputmechanisms. In the first, Mauro Zordan, EzioRosato, Alberto Piccin and Russel Foster review therelevant characteristics of the photic environmentand compare the properties of some relevantphotopigments. Their analysis also focuses on thedetails of circadian photic input in Drosophila, thestate of affairs in mammals, as well as on phylogeneticconsiderations concerning the appearance andevolution of anatomical structures and/or pigmentsinvolved in photic entrainment.

Finally, Paul Taghert centres his attention on theproximate aspects of the neuronal clock outputsand on how the circadian clock signals timingto the brain. In particular, he analyses the roleof PDF (the neuropeptide pigment-dispersingfactor) in Drosophila as the principle transmitterof primary pacemakers. His review concerns theemerging mechanisms of PDF regulation, withina subset of the small lateral neurons (LN-v’s),which are positively mediated by the clock proteinsCLOCK and CYC, while PER and TIM are probablyinvolved in posttranslational regulation of PDF. Inspite of its obvious involvement in clock output,opinions remain divided on a possible role for PDFin non photic input to the clock. Other per/timexpressing neurons, (not the LN-v’s), may alsocontribute pacemaker activity by releasing other

Figure 1. Francesco Clemente, Contemplation 1990.Sezon Museum of Modern Art, Japan.

neurotransmitters. As for mammals, the role of a sub-area of the SCN core, which following transplantationconfers behavioural rhythmicity to surgically ablated(SCN-X) rodents, is discussed. It is suggested that thissub-region may contain a special class of pacemakingneurons whose identity is still uncertain, but whichare labelled by CalbindinD-28K immunostaining.

Circadian 24 hour rhythms percolate every aspectof human behaviour, physiology and cognitivefunctioning. Approximately a quarter of thepopulation living in industrialized areas workshifts and suffers concomitant health problems,both physical and psychological, that have a highsocial and economic cost. Apart from work-relatedenvironmental disturbances to the clock, mutationsin human clock components can have equallydisruptive effects5 (Figure 1, a gouache by FrancescoClemente, nicely evokes this clock disturbance, aphase advance which dramatically affects sleep).The circadian clock represents a very significantcomponent for human health and well-being that hasbeen largely ignored by the medical community.The completion of the genome sequencingprogrammes for a number of model organisms(including Drosophila and man), together with theavailability of the new and extremely powerful DNA-microarray technologies, will, sooner rather thanlater, significantly enhance our understanding of thecircadian clock. The next few years thus promiseto be a particularly exciting time in this area offundamental biological and behavioural research,

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and will doubtless require the services of additionalreviewers to allow us to keep pace with all of thesedevelopments.

References

1. Dunlap JC (1999) Molecular bases for circadian clocks. Cell96:271–290

2. Scully AL, Kay SA (2000) Time flies for Drosophila. Cell100:297–300

3. Balsalobre A, Damiola F, Schibler U (1998) A serum shockinduces circadian gene expression in mammalian tissueculture cells. Cell 93:929–937

4. Reppert SM, Weaver DR (2000) Comparing clockworks:mouse versus fly. J Biol Rhythms 15:357–364

5. Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM,Ptacek LJ, Fu YH (2001) An hPer2 phosphorylation sitemutation in familial advanced sleep phase syndrome. Science291:1040–1043

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