Journal of Experimental Botany, Vol. 53, No. 374, pp. 1551-1557,
July 1, 2002
© 2002 Oxford University Press
MYB transcription factors in the Arabidopsis circadian clock
Received 25 September 2001; Accepted 25 April 2002
1 Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, UK
3 Present address: Cold-Spring Harbor Laboratory, 1 Bungtown Road, Cold-Spring Harbor, NY 11 724, USA.
 |
Abstract |
|---|
 Top Abstract IntroductionReferences |
|---|
The LATE ELONGATED HYPOCOTYL (LHY) and CIRCADIAN CLOCK ASSOCIATED (CCA1) genes encode closely related MYB transcription factors, which regulate circadian rhythms in Arabidopsis. LHY and CCA1 verify some of the properties of oscillator components, since (i) expression of their transcripts and protein exhibits circadian oscillations; (ii) their constitutive expression abolishes overt rhythmicity and (iii) they function as components of a negative transcriptional feedback loop. LHY and CCA1 have been proposed to function in conjunction with the pseudo response regulator TOC1, as components of the circadian oscillator. The regulation of their respective transcripts and protein levels in response to light signals suggests that these proteins may also mediate the regulation of circadian rhythms by light. This review discusses experimental evidence for these hypotheses.
Key words: Key words: Arabidopsis, circadian clock, light, MYB transcription factors, temperature.
|
Introduction |
|---|
|
TopAbstractIntroductionReferences |
|---|
The impact of circadian rhythms on physiology is better characterized in plants than in any other system (Harmer et al., 2000), but the molecular mechanism of the underlying oscillator is not yet understood. Genetic approaches in model organisms, such as Neurospora, Drosophila, mice, and cyanobacteria, have identified the molecular components of their respective circadian clocks (reviewed in Dunlap, 1999; Bell-Pedersen, 2000; Young, 1998; Scully and Kay, 2000; Whitmore et al., 2000; Reppert and Weaver, 2000; Kondo and Ishiura, 2000). Similar approaches have been undertaken more recently in Arabidopsis, and at least 20 genetic loci have been shown to regulate the function of the circadian clock (see Roden and Carré, 2001, for a review). A number of the cognate genes have been cloned (Schaffer et al., 1998; Wang and Tobin, 1998; Fowler et al., 1999; Strayer et al., 2000; Somers et al., 2000). However, so far, none of these genes encode orthologues of clock components from any other system and it is not known at present how they interact to generate circadian rhythms.
Conceptually, the circadian system can be divided into three components. Circadian time-keeping is mediated by a central oscillator, which is thought to consist of a biochemical feedback loop. To be useful as a clock, this oscillator has to be set to local time. The environmental cues that set the phase of the clock are usually light and temperature, and the signal transduction pathways that reset the clock in response to these signals are known as input pathways. Downstream of the oscillator, other signal transduction pathways, known as output pathways, mediate the control of overt rhythms. Many of the loci that regulate the function of the Arabidopsis clock appear to function in light input (Roden and Carré, 2001; Devlin, 2002), but so far only three genes have been proposed to function as components of the circadian oscillator. The TIMING OF CAB 1 (TOC1) gene has also been described as ARABIDOPSIS PSEUDO RESPONSE REGULATOR 1 (APRR1). It comprises a sequence that is related to the receiver domain of two component-signalling systems of plants and animals, and a region that is similar to the flowering time regulator CONSTANS (Strayer et al., 2000; Makino et al., 2000). The two other putative oscillator genes encode closely related transcription factors of the MYB family, LHY and CCA1. This paper describes the experimental approaches that enabled the identification of these candidate clock genes and the rationale used to probe their functions in the Arabidopsis circadian clock. This review aims to be accessible, rather than exhaustive, and apologies are extended to those whose work has not been mentioned here. More detailed overviews of the plant circadian field have been published elsewhere (McClung, 2001; Roden and Carré, 2001).
Identification of circadian clock mutants in Arabidopsis
The isolation of mutants in any process requires a phenotype that can be scored easily, reliably and in a non-invasive manner. Arabidopsis mutants with deficient circadian clocks have been identified by different methods. First, transgenic plants were produced that carried a firefly luciferase reporter gene (luc) under the control of the circadian-regulated CAB (CHLOROPHYLL a/b-BINDING PROTEIN) promoter. The activity of the luciferase reporter gene was rhythmic in these plants, and could be measured in vivo using a photon-counting camera (Millar et al., 1992). These transgenic plants were then mutagenized using EMS and their M2 progeny was screened for abnormal rhythms of bioluminescence in constant light (LL). This screen resulted in the isolation of a number of long and short period mutants (Millar et al., 1995). The toc1 mutant was particularly interesting as its circadian phenotypes were completely independent of illumination conditions (Somers et al., 1998). The mutation shortened the free-running rhythm of cab:luc expression to similar degrees under all fluences of light. When plants were grown under 24 h light/dark cycles, the peak of CAB gene expression was advanced in toc1 relative to the wild type. This phase defect was argued to reflect the abnormal function of the central oscillator, rather than aberrant light input to the clock, because a similarly altered phase was observed in constant light under 24 h temperature cycles.
Another set of mutants was identified by their abnormal flowering time phenotypes. Many plants and animals enter their reproductive phase at specific times of the year, and the perception of changes in seasons relies primarily on the measurement of daylength, or photoperiod. The measurement of photoperiod is though to be mediated by a circadian clock (Carré, 2001), therefore a subset of mutations that cause abnormal floral responses to daylength were expected to cause abnormal circadian rhythms. For example, the early flowering 3 (elf3) mutant flowered much earlier than wild-type plants under short-day photoperiods (8L16D, the alternation of 8 h of light and 16 h of darkness). elf3 was a very good candidate for a clock mutant, since it flowered at the same time and at the same developmental stage, regardless of photoperiod. The cab:luc reporter gene was introduced into the elf3 mutant by genetic crossing, and its expression was monitored under different light/dark conditions. Interestingly, cab:luc expression was arrhythmic in elf3 plants under constant light conditions, suggesting that the function of their circadian clock was disrupted (Hicks et al., 1996). But elf3 mutant plants exhibited rhythmic cab:luc expression under diurnal light/dark cycles, and these oscillations persisted for one to two cycles following transfer to constant darkness (DD). This result indicated that ELF3 function was not required for circadian oscillations. Since the arrhythmic phenotype of the elf3 mutant was conditional upon constant illumination of the plants, the mutation was proposed to alter the regulation of the circadian clock by light (Hicks et al., 1996; McWatters et al., 2000).
Like elf3, the late elongated hypocotyl (lhy) mutant exhibited daylength-insensitive flowering, but its flowering time was intermediate between that of wild-type plants grown under short or long days (Schaffer, 1997). Circadian rhythms of leaf movements were abolished by the lhy mutation, and cab:luc expression was arrhythmic in LL and in DD. In addition, the lhy mutation disrupted the rhythmic expression of the CCR2 (COLD-CIRCADIAN RHYTHM-RNA-BINDING) gene, which normally peaks in the evening, several h after CAB (Schaffer et al., 1998). Since the lhy mutation disrupted several overt rhythms and the oscillation of genes that peaked at different times of the day, it was unlikely to disrupt the function of a specific output pathway. This suggested that the LHY gene may either mediate or regulate the function of the circadian oscillator.
LHY and the closely related gene CCA1 may encode redundant components of a negative transcriptional feedback loop
The lhy mutation was caused by the insertion of a transposon (Ds) within the 5' untranslated region (5'UTR) of the LHY gene. The Ds element comprised a strong promoter (35S, from the cauliflower mosaic virus) which caused the overexpression of the adjacent open reading frame. Transformation of wild-type plants with a cosmid clone comprising the Ds element and the adjacent open reading frame was sufficient to reproduce the effect of the lhy mutation in transgenic plants. These results, and the dominant nature of the lhy mutation suggested that it resulted from a gain of function allele, caused by the overexpression of the LHY gene (Schaffer et al., 1998).
The amino acid sequence of LHY revealed homology to the MYB family of transcription factors. However, LHY encoded an unusual member since its DNA-binding domain comprised a single MYB repeat instead of two or three as in most MYB proteins (Jin and Martin, 1999). It showed a high level of similarity to CCA1 (CIRCADIAN CLOCK-ASSOCIATED-1), a protein that bound to a conserved light-regulated element of the Arabidopsis CAB (Lhcb1*3) gene (Wang et al., 1997). LHY and CCA1 have virtually identical DNA-binding domains, and show strong homology throughout their protein sequences (Schaffer et al., 1998). CCA1 was also shown to play a role similar to that of LHY, in the regulation of circadian rhythms. As with LHY, overexpression of the CCA1 transcript under the control of the 35S promoter abolished the rhythmic expression of CAB, CCR2 and CATALASE 3 (CAT3) (Wang and Tobin, 1998).
The LHY and CCA1 transcripts were both expressed rhythmically, and peaked shortly after dawn. These rhythms persisted in constant light and in constant darkness, showing that both genes were under circadian control (Schaffer et al., 1998; Wang and Tobin, 1998). The rhythmic expression of the LHY and CCA1 mRNAs was abolished in lhy1 and CCA1-overexpressing (CCA1-ox) plants, respectively. Since the constitutive expression of these transcripts correlated with arrhythmic phenotypes, the rhythmic expression of LHY and CCA1 was suggested to be required for the expression of circadian rhythmicity.
Intriguingly, LHY and CCA1 regulated their own expression, as well as each other’s. Plants that carried a transgenic, overexpressed copy of either gene exhibited arrhythmic expression of the endogenous LHY and CCA1 transcripts. Furthermore, the expression of both endogenous genes was repressed to the trough level of wild-type plants. These results suggested that LHY and CCA1 may function redundantly as components of a negative feedback loop (Schaffer et al., 1998; Wang and Tobin, 1998).
LHY and CCA1 exhibit properties of circadian oscillator components
Oscillatory feedback loops have been found at the core of all circadian clock mechanisms examined so far (Dunlap, 1999). Negative feedback loops are known to give rise to oscillations and are thought to constitute the timing component of circadian systems. Therefore, the observation that LHY and CCA1 negatively regulated the expression of their own transcripts was provocative, since it suggested that they may both function as part of the circadian oscillator. However, plants that carried loss of function mutations in the LHY or CCA1 genes exhibited robust rhythms of gene expression and leaf movements (Green and Tobin, 1999; Mizugochi et al., 2002). The period of the rhythms was shortened by 2–3 h, but circadian rhythmicity was otherwise not impaired. Thus, neither LHY nor CCA1 were required for the function of the circadian oscillator. However, the similarities between these two proteins suggested that they might be able to substitute for each other’s function. To test this hypothesis, double mutants lacking functional copies of both genes were constructed. These lhy-11 cca1-1 plants exhibited diurnal rhythms of gene expression (lhy:luc, cca1:luc, and ccr2:luc) with an abnormal phase, but the amplitude of these rhythms was gradually reduced and no significant oscillations of transcript levels were detected on RNA blots after 3 d in constant light (Mizugochi et al., 2002). A similar loss of circadian rhythmicity was observed after transfer to constant darkness, suggesting that this phenotype did not reflect aberrant light input to the clock (Hae-Ryong Song and Isabelle Carré, unpublished results). When grown under light/dark cycles, the lhy-11, cca1-1 and double knock-out mutants also exhibited an early phase of expression of both morning (LHY, CCA1) and evening (CCR2) genes. As previously described for toc1, a similar phase alteration was observed under temperature cycles. These results indicated that the lhy-11 and cca1-1 mutations altered the properties of the central oscillator, rather than its regulation by specific input pathways.
Reciprocal regulation between LHY/CCA1 and TOC1
What is the function of LHY and CCA1 within the circadian clock? When a construct comprising the coding region of LHY fused to the green fluorescent protein (GFP) was transformed into onion or Arabidopsis cells, fluorescence was localized to the nucleus (Fig. 1). The nuclear localization of LHY is consistent with its proposed function as a transcription factor. Furthermore, LHY and CCA1 were shown to bind specifically a DNA sequence that is found within the promoter of many rhythmic genes that peak near dusk (Alabadi et al., 2001; Harmer et al., 2000). Interestingly, this ‘evening element’ (EE) was present within the promoter of the putative oscillator component TOC1. This suggested that LHY and CCA1 might regulate TOC1 expression in a direct manner.
|
In wild-type plants, expression of the TOC1 transcript exhibited circadian oscillations (Strayer et al., 2000). Maximum transcription of TOC1 at dusk coincided with minimal expression of LHY and CCA1 proteins. In plants that overexpressed either LHY or CCA1, TOC1 expression was arrhythmic in constant light. Most importantly, it was repressed to a level close to the trough of the wild-type rhythm. This result suggested that LHY and CCA1 inhibit transcription from the TOC1 promoter (Alabadi et al., 2001).
The reciprocal regulation of clock-associated genes is central to the function of all circadian oscillators (Dunlap, 1999). It was therefore important to test whether TOC1 regulated transcription from the LHY and CCA1 promoters. Expression of both LHY and CCA1 transcripts was reduced in a presumed loss-of function allele, toc1-2, suggesting that TOC1 may function as a positive effector of LHY and CCA1 expression (Alabadi et al., 2001). It is not known at this point whether this regulation is direct or not. The TOC1 protein does not exhibit any recognizable feature that would mediate its binding to DNA. It is therefore likely that its function requires one or more protein partners.
A working model for the Arabidopsis circadian clock
The results discussed above suggested that the MYB transcription factors LHY and CCA1 might function as the negative elements of a transcriptional feedback loop, a role similar to those of PERIOD (PER) and TIMELESS (TIM) in Drosophila, or FREQUENCY (FRQ) in Neurospora. TOC1 might function as a positive element, a role similar to those of CLOCK (CLK) and (CYCLE (CYC) in Drosophila, or WHITE COLLAR 1 and 2 (WC1 and WC2) in Neurospora. Alabadi and colleagues (2001) proposed that the reciprocal regulation between TOC1 and LHY/CCA1 might define the basic framework for the clock mechanism in Arabidopsis (Fig. 2). Expression of the negative elements (LHY and CCA1) in the morning would repress expression of the positive element (TOC1), leading to a decay in LHY and CCA1 transcript levels in the course of the day. Decreasing levels of CCA1 and LHY protein would mediate the derepression of the TOC1 gene and allow its transcription to resume in the early evening. The subsequent accumulation of TOC1 protein at night would result in increased transcription from the LHY and CCA1 promoters, through an unknown mechanism.
|
Entrainment to light/dark cycles
In natural conditions the phase of circadian oscillations is locked to that of environmental cycles, a phenomenon known as ‘entrainment’. The entrainment of circadian clocks to light/dark cycles is generally mediated by light-induced changes in the level of a component of the oscillatory feedback loop. Thus, in Neurospora, light induced increases in the level of FRQ transcript. By contrast, the effects of light on the Drosophila clock were mediated by light-induced decreases in the level of TIM protein. Thus, if LHY and CCA1 function as elements of the circadian oscillator, light-induced increases in their expression levels would be expected to reset the phase of the clock.
CCA1 was orginally identified as a protein that mediated the regulation of CAB transcription by light (Wang et al., 1997). In etiolated seedlings, expression of the CCA1 transcript was induced by red light, and transgenic plants that carried an antisense CCA1 construct exhibited reduced induction of their endogenous CAB gene. A similar pattern of light induction in etiolated plants was reported for LHY (Martinez-Garcia et al., 2000). However, in light-grown plants, the regulation of LHY expression by light was mainly post-translational (Jae-Yean Kim, Hae-Ryong Song and Isabelle Carré, unpublished results). In plants that carried a constitutively transcribed copy of the gene, the LHY protein accumulated in response to light. This accumulation was caused by the increased rate of accumulation of the protein, rather than by its accelerated turnover. The translational induction of LHY by light was only observed at specific phases of the circadian cycles, however, as it was limited to times when the transcript was already present (around dawn). It is not known yet whether the effects of light on expression of the CCA1 protein are gated in the same manner.
If LHY plays a role in the resetting of the clock in response to light signals, maximum phase-shifting responses should coincide with times when LHY expression is most inducible. Light pulses perceived early in the night caused phase advances, and similar signals given late in the night induced phase delays (Covington et al., 2001; Jae-Yean Kim, Hae-Ryong Song and Isabelle Carré, unpublished results). The greatest responses were observed in the middle of the night (CT18), a phase clearly distinct from that when LHY expression was responsive to light (ZT1). These results suggest that the induction of LHY by night does not mediate entrainment of the clock to light/dark cycles. Light-induced increases of LHY levels at dawn may serve to maintain high amplitude oscillations of the central pacemaker. Alternatively they may serve to regulate the amplitude of oscillation of output genes such as CAB, that exhibits dual regulation by light as well as by the clock.
Further levels of complexity
If, as proposed here, LHY and CCA1 function as components of the oscillator, the observation that the double knock-out mutant (lhy-11 cca1-1) retained circadian rhythmicity is puzzling. The damped rhythmicity exhibited by lhy-1 cca1-1 double mutants upon transfer to free-running conditions was reminiscent of the phenotypes of mice lacking one redundant component of their circadian clock. The mPer 1, 2 and 3 genes function as components of a negative transcriptional feedback loop, which is thought to mediate circadian rhythmicity in mice (Whitmore et al., 2000). A mper2 knockout strain of mice was isolated, and these mice exhibited rhythmic wheel-running behaviour under diurnal light/dark cycles, which damped out progressively upon transfer to constant darkness (Zheng et al., 1999). The residual function of the circadian clock in mper2 mutant mice is thought to be mediated by mPer1 and mPer3. Similarly, in Arabidopsis, functional redundancy may extend beyond LHY and CCA1. Other MYB transcription factors may also regulate the expression of LHY and CCA1 target genes to allow the impaired but indisputable function of the circadian clock in lhy1-1 cca1-1 double mutants. Now that the genome of Arabidopsis has been fully sequenced, it is known that several additional proteins exhibit sequence similarity within the MYB DNA-binding domain (Fig. 3). These proteins may be able to bind the same targets as LHY and CCA1. Interestingly, some members of this gene family were also expressed in a circadian fashion (Strayer and Kay, 1999). It will be necessary to knock out each of these genes, alone and in combination with others, in order to determine whether their function might overlap with that of CCA1 and LHY within the circadian oscillator.
|
The model proposed in Fig. 2 for the mechanism of the Arabidopsis clock is satisfying at first sight, because it fits well within the framework established for circadian clock mechanisms of other organisms. But less than a year after its publication by Alabadi and colleagues, new data indicate that it is insufficient to explain mutant phenotypes and to describe the regulatory interactions between known clock components. For example, the constitutive overexpression of TOC1 would be expected to cause an arrhythmic phenotype, as previously shown for LHY and CCA1. Yet, overexexpression of TOC1 in transgenic plants did not abolish circadian oscillations, although the amplitude of gene expression rhythms was reduced (Makino et al., 2002). The rhythmic phenotype of TOC1-overexpressing plants might be explained, if TOC1 function requires association with a protein partner that is also expressed rhythmically. However, such a partner remains to be identified. What is more confusing is that expression of LHY and CCA1 transcripts in these plants was repressed to the trough of the wild-type rhythm, instead of increased as predicted by the model. On the other hand, plants that lacked LHY or CCA1 function or both, displayed reduced (rather than increased) levels of expression of lhy:luc and cca1:luc reporter fusions (Bethan Taylor, Hae-Ryong Song and Isabelle Carré, unpublished results). These results do not necessarily rule out the hypothesis that the LHY1, CCA1 and TOC1 exhibit the cross-regulation described in Fig. 2, but they suggest that the core mechanism of the plant circadian oscillator comprises additional levels of regulation.
The circadian oscillator of Arabidopsis might comprise multiple loops, mediating positive as well as negative feedback. Such interlocked feedback loops have been described within the circadian clocks of fungi, flies and mammals (Lee et al., 2000; Shearman et al., 2000; Glossop et al., 1999). Thus, the damped circadian oscillations in lhy1-1 cca1-1 double mutants may represent the function of a feedback loop that would normally interact with the LHY/CCA1/TOC1 feedback loop, but that is capable of oscillatory behaviour in its absence. Faced with such complexity, it may be time to throw away all of the preconceptions of how clock genes should behave, and focus on analysing the network of regulatory interactions between clock-associated genes. The recent identification of several of these genes provided the first tools to approach these questions at the molecular level, and it is now possible to begin assembling the pieces of the puzzle.
|
Acknowledgements |
|---|
We thank George Coupland for communication of results prior to publication. IC was supported by a fellowship from the University of Warwick, and research in her laboratory is funded by the BBSRC and the Royal Society.
|
References |
|---|
|
TopAbstractIntroductionReferences |
|---|
Alabadi D, Oyama T, Yanovsky MJ, Harmon FG, Mas P, Kay SA. 2001. Reciprocal regulation between TOC1 and LHY/CCA1 within the Arabidopsis circadian clock. Science 293, 880–883.
Bell-Pedersen D. 2000. Understanding circadian rhythmicity in Neurospora crassa: from behavior to genes and back again. Fungal Genetics and Biology 29, 1–18.[Web of Science][Medline]
Carré IA. 2001. Daylength perception and the photoperiodic regulation of flowering in Arabidopsis. The Journal of Biological Rhythms 16, 415–423.
Corpet F, Servant F, Gouzy J, Kahn D. 2000. ProDom and ProDom-CG: tools for protein domain analysis and whole genome comparisons. Nucleic Acids Research 28, 267–269.
Covington MF, Panda S, Liu XL, Strayer CS, Wagner DR, Kay SA. 2001. ELF3 modulates resetting of the circadian clock in Arabidopsis. The Plant Cell 13, 1305–1315.
Devlin PF. 2002. Signs of the time: environmental input to the circadian clock. Journal of Experimental Botany 53, 000–000.
Dunlap JC. 1999. Molecular bases for circadian clocks. Cell 96, 271–290.[Web of Science][Medline]
Fowler S, Lee K, Onouchi H, Samach A, Richardson K, Morris B, Coupland G, Putterill J. 1999. GIGANTEA: a circadian clock-controlled gene that regulates photoperiodic flowering in Arabidopsis and encodes a protein with several possible membrane-spanning domains. EMBO Journal 18, 4679–4688.[Web of Science][Medline]
Glossop NRJ, Lyons LC, Hardin PE. 1999. Interlocked feedback loops within the Drosophila circadian oscillator. Science 286, 766–771.
Green RM, Tobin EM. 1999. Loss of the CIRCADIAN CLOCK-ASSOCIATED protein 1 in Arabidopsis results in altered clock-regulated gene expression. Proceedings of the National Academy of Sciences, USA 96, 4176–4179.
Harmer SL, Hogenesch JB, Straume M, Chang H-S, Han B, Zhu T, Wang X, Kreps JA, Kay SA. 2000. Orchestrated transcription of key pathways in Arabidopsis by the circadian clock. Science 290, 2110–2113.
Hicks KA, Millar AJ, Carré IA, Somers DE, Straume M, Meeks-Wagner DR, Kay SA. 1996. Conditional circadian dysfunction of the Arabidopsis early-flowering 3 mutant. Science 274, 790–792.
Jin H, Martin C. 1999. Mutifunctionality and diversity within the plant MYB gene family. Plant Molecular Biology 41, 577–585.[Web of Science][Medline]
Kim JY, Yuan Z, Cilia M, Khalfan Z, Jackson D. 2002. Intercellular trafficking of a biologically active KNOTTED1-green fluorescent protein fusion in Arabidopsis. Proceedings of the National Academy of Sciences, USA 99, 4103–4108.
Kondo T, Ishiura M. 2000. The circadian clock of cyanobacteria. BioEssays 22, 10–15.[Web of Science][Medline]
Lee K, Loros JJ, Dunlap JC. 2000. Interconnected feedback loops in the Neurospora circadian system. Science 289, 107–110.
Makino S, Kiba T, Imamura A, Hanaki N, Nakamura A, Suzuki T, Taniguchi M, Ueguchi C, Sugiyama T, Mizuno T. 2000. Genes encoding pseudo-response regulators: insight into his-to-Asp phosphorelay and circadian rhythms in Arabidopsis thaliana. Plant and Cell Physiology 41, 791–803.
Makino S, Matsushika A, Kojima M, Yamashino T, Mizuno T. 2002. The APRR1/TOC1 quintet implicated in circadian rhythms of Arabidopsis thaliana. I. Characterization with APRR1-overexpressing plants. Plant and Cell Physiology 43, 58–69.
Martinez-Garcia JF, Huq E, Quail PH. 2000. Direct targeting of light signals to a promoter element-bound transcription factor. Science 288, 859–863.
McClung CR. 2001. Circadian rhythms in plants. Annual Review of Plant Physiology and Plant Molecular Biology 52, 139–162.[Web of Science][Medline]
McWatters HG, Bastow RM, Hall A, Millar AJ. 2000. The ELF3 zeitnehmer regulates light signalling to the circadian clock. Nature 408, 716–719.[Medline]
Millar AJ, Carré IA, Strayer CA, Chua N-H, Kay SA. 1995. Circadian clock mutants in Arabidopsis identified by luciferase imaging. Science 267, 1161–1163.
Millar AJ, Short SR, Chua N-H, Kay SA. 1992. A novel circadian phenotype based on firefly luciferase expression in transgenic plants. The Plant Cell 4, 1075–1087.
Mizugochi T, Wheatley K, Wright L, Hanzawa Y, Song H-R, Carré IA, Coupland G. 2002. LHY and CCA1 are partially redundant genes required to maintain circadian rhythms in Arabidopsis. Developmental Cell (in press).
Reppert SM, Weaver DR. 2000. Comparing clockworks: mouse versus fly. The Journal of Biological Rhythms 15, 357–364.
Roden LC, Carré IA. 2001. The molecular genetics of circadian rhythms in Arabidopsis. Seminars in Cellular and Developmental Biology 12, 305–315.
Schaffer R. 1997. LHY, a gene that regulates flowering and hypocotyl elongation of Arabidopsis. Norwich, UK: University of East Anglia.
Schaffer R, Ramsay N, Samach A, Corden S, Putterill J, Carré IA, Coupland G. 1998. The LATE ELONGATED HYPOCOTYL mutation of Arabidopsis disrupts circadian rhythms and the photoperiodic control of flowering. Cell 93, 1219–1229.[Web of Science][Medline]
Scully AL, Kay, SA. 2000. Time flies for Drosophila. Cell 100, 297–300.[Web of Science][Medline]
Shearman LP, Sathyanarayanan S, Weaver DR, Maywood ES, Chaves I, Zheng B, Kume K, Lee CC, Van der Horst GTJ, Hastings MH, Reppert SM. 2000. Interacting molecular loops in the mammalian circadian clock. Science 288, 1013–1019.
Somers DE, Schultz TF, Milnamow M, Kay SA. 2000. Zeitlupe encodes a novel clock-associated pas protein from Arabidopsis. Cell 101, 319–329.[Web of Science][Medline]
Somers DE, Webb AAR, Pearson M, Kay SA. 1998. The short-period mutant, toc1-1, alters circadian clock regulation of multiple outputs throughout development in Arabidopsis thaliana. Development 125, 485–494.[Abstract]
Strayer CA, Kay SA. 1999. The ins and outs of circadian-regulated gene expression. Current Opinions in Plant Biology 2, 114–120.[Web of Science][Medline]
Strayer C, Oyama T, Schultz TF, Raman R, Somers DE, Mas P, Panda S, Kreps JA, Kay SA. 2000. Cloning of the Arabidopsis clock gene TOC1, an autoregulatory response regulator homolog. Science 289, 768–771.
Wang Z-Y, Kenigsbuch D, Sun L, Harel E, Ong MS, Tobin EM. 1997. A MYB-related transcription factor is involved in the phytochrome regulation of an Arabidopsis lhcb gene. The Plant Cell 9, 491–507.[Abstract]
Wang Z-Y, Tobin EM. 1998. Constitutive expression of the CIRCADIAN CLOCK ASSOCIATED (CCA1) gene disrupts circadian rhythms and suppresses its own expression. Cell 93, 1207–1217.[Web of Science][Medline]
Whitmore D, Cermakian N, Crosio C, Foulkes NS, Pando MP, Travnickova Z, Sassone-Corsi P. 2000. A clockwork organ. Biological Chemistry 381, 793–800.[Web of Science][Medline]
Young MW. 1998. The molecular control of circadian behavioral rhythms and their entrainment in Drosophila. Annual Review of Biochemistry 67, 135–152.[Web of Science][Medline]
Zheng B, Larkin DW, Albrecht U, Sun ZS, Sage M, Eichele G, Lee CC, Bradley A. 1999. The mPer2 gene encodes a functional component of the mammalian circadian clock. Nature 400, 169–173.[Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. X. Lu, S. M. Knowles, C. Andronis, M. S. Ong, and E. M. Tobin CIRCADIAN CLOCK ASSOCIATED1 and LATE ELONGATED HYPOCOTYL Function Synergistically in the Circadian Clock of Arabidopsis Plant Physiology, June 1, 2009; 150(2): 834 - 843. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Yakir, D. Hilman, I. Kron, M. Hassidim, N. Melamed-Book, and R. M. Green Posttranslational Regulation of CIRCADIAN CLOCK ASSOCIATED1 in the Circadian Oscillator of Arabidopsis Plant Physiology, June 1, 2009; 150(2): 844 - 857. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Fujiwara, A. Oda, R. Yoshida, K. Niinuma, K. Miyata, Y. Tomozoe, T. Tajima, M. Nakagawa, K. Hayashi, G. Coupland, et al. Circadian Clock Proteins LHY and CCA1 Regulate SVP Protein Accumulation to Control Flowering in Arabidopsis PLANT CELL, November 1, 2008; 20(11): 2960 - 2971. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. W. Manfield, C.-H. Jen, J. W. Pinney, I. Michalopoulos, J. R. Bradford, P. M. Gilmartin, and D. R. Westhead Arabidopsis Co-expression Tool (ACT): web server tools for microarray-based gene expression analysis. Nucleic Acids Res., July 1, 2006; 34(Web Server issue): W504 - W509. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. P. Hazen, T. F. Schultz, J. L. Pruneda-Paz, J. O. Borevitz, J. R. Ecker, and S. A. Kay LUX ARRHYTHMO encodes a Myb domain protein essential for circadian rhythms PNAS, July 19, 2005; 102(29): 10387 - 10392. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. E. Somers, W.-Y. Kim, and R. Geng The F-Box Protein ZEITLUPE Confers Dosage-Dependent Control on the Circadian Clock, Photomorphogenesis, and Flowering Time PLANT CELL, March 1, 2004; 16(3): 769 - 782. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Kuno, S. G. Moller, T. Shinomura, X. Xu, N.-H. Chua, and M. Furuya The Novel MYB Protein EARLY-PHYTOCHROME-RESPONSIVE1 Is a Component of a Slave Circadian Oscillator in Arabidopsis PLANT CELL, October 1, 2003; 15(10): 2476 - 2488. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Eriksson and A. J. Millar The Circadian Clock. A Plant's Best Friend in a Spinning World Plant Physiology, June 1, 2003; 132(2): 732 - 738. [Full Text] [PDF]
|
|
|
|
 |
|
 P. F. Devlin Signs of the time: environmental input to the circadian clock J. Exp. Bot., July 1, 2002; 53(374): 1535 - 1550. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||