Department of Biology and Biochemistry, University of Houston, 369 Science and Research 2 Bldg., Houston, TX 77204-5001, USA
* Author for correspondence (e-mail: phardin{at}uh.edu)
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Summary |
---|
Key words: Circadian clock, Drosophila, Mouse, Molecular mechanisms, Genetics
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Introduction |
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In mammals the central `master' clock is located in the suprachiasmatic
nucleus (SCN) of the anterior hypothalamus
(Klein et al., 1991). The SCN
is entrained to light-dark (LD) cycles by a distinct set of photosensitive
retinal ganglion cells that project to the SCN through the retinohypothalamic
tract (Berson et al., 2002
;
Hattar et al., 2002
;
Moore et al., 1995
;
Provencio et al., 2002
). The
SCN in turn activates rhythms in behavior (e.g. locomotor activity), by
secreting factors (e.g. TGF
and prokineticin) that act locally within
the hypothalamus (Cheng et al.,
2002
; Kramer et al.,
2001
), and entrains subservient circadian oscillators in
peripheral tissues (e.g. liver and kidney) via humoral signals (e.g.
glucocorticoids) (Balsalobre et al.,
2000a
; Balsalobre et al.,
2000b
; Oishi et al.,
1998
; Ueyama et al.,
1999
). Such peripheral oscillators can, however, become uncoupled
from the SCN if their specific needs dictate as occurs in liver, lung
and skeletal muscle after entrainment by food
(Yamazaki et al., 2000
). The
SCN maintains robust (>2 week) rhythms when entrained to LD cycles in vivo
and cultured in vitro, whereas peripheral oscillators lose rhythmicity after
just 4-5 days under the same conditions
(Yamazaki et al., 2000
).
In flies the central clock is located in a group of 5-6 bilaterally
symmetric small ventral lateral neurons (sLNvs) situated in the
lateral brain close to the optic lobes
(Helfrich-Forster, 1996). As
in the SCN, sLNvs receive light input from retinal photoreceptors
in the compound eyes and extra-retinal photoreceptors within the brain;
however, they can also be entrained directly by light that penetrates the
cuticle (Helfrich-Forster et al.,
2001
; Stanewsky et al.,
1998
). In constant dark (DD) conditions, sLNvs maintain
robust rhythms in gene expression and locomotor activity
(Ewer et al., 1992
;
Frisch et al., 1994
;
Helfrich-Forster, 1998
;
Zerr et al., 1990
).
Peripheral oscillators in flies (e.g. antennal clock cells and Malpighian
tubules) can also maintain robust (>7 day) rhythms in cell culture, which
suggests that fly peripheral oscillators depend less on the sLNvs
than do their mammalian counterparts on the SCN
(Emery et al., 1997
;
Giebultowicz and Hege, 1997
;
Plautz et al., 1997
). Indeed,
precisely how much influence the sLNvs have over fly peripheral
oscillators is not known, given that light penetrating through the cuticle
appears to entrain peripheral clocks, thus negating the requirement for a
`master' clock to synchronize other oscillators in the fly. Despite this
difference, the sLNvs can be regarded as a central oscillator
because, like the SCN, they drive behavioral rhythms in locomotor
activity.
The core components involved in central and peripheral clocks of flies and mammals are largely conserved and in both they form interlocked feedback loops in transcription/translation (Fig. 1, Table 1). In flies, most of the information regarding the oscillator mechanism has derived from studies of mRNA and protein levels in whole head extracts. As such, the majority of information concerns oscillators in head peripheral tissues (i.e. photoreceptors and antennae), because the sLNvs make up only a small percentage (<1%) of the total number of oscillators in the head. In mammals, however, previous work focused primarily on the central SCN oscillator because of the desire to link it to the behavioral rhythm in locomotor activity. Daily fluctuations in mRNA and protein levels can also be readily monitored in the SCN, whereas a similar examination of most clock components in the fly sLNvs is not possible. Thus, previous comparisons between these species have largely compared fly peripheral oscillators with the mouse central oscillator.
|
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Although the two systems show striking similarities, they also show some equally important differences. Here we outline current understanding of the fly peripheral and mouse central oscillators, paying particular attention to the differences between the two. We then consider more recent findings that suggest that peripheral oscillators of mammals share more in common with those of the fly than the mammalian central oscillator and, hence, that the central oscillators of both organisms may have acquired novel regulatory features that make them specialized versions of a more basic design.
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The fly peripheral oscillator |
---|
Light entrains the oscillator through a blue-light-responsive
pterin/flavin-binding protein, cryptochrome (CRY)
(Fig. 1A;
Table 1). CRY can bind TIM in
response to light, ultimately causing TIM degradation and predictable phase
advances or delays in the oscillator
(Hunter-Ensor et al., 1996;
Lee et al., 1996
;
Myers et al., 1996
;
Saunders et al., 1994
;
Zeng et al., 1996
).
Transcription of cry is also under control of the oscillator
(Table 1). The cry
mRNA profile reflects that of dClk, albeit delayed by several hours
(Egan et al., 1999
;
Emery et al., 1998
;
Ishikawa et al., 1999
).
cry and dClk mRNA levels are similarly perturbed in several
clock mutants. In dClkJrk and
cyc01 mutants, dClk and cry
mRNAs are constitutively high, whereas in per01
and tim01 mutants dClk and cry
are constitutively low (Emery et al.,
1998
). This suggests that cry and dClk are under
similar transcriptional regulation. Unlike the robust per/tim
oscillations, cry mRNA oscillations dampen quickly, tending to trough
levels by the third day in DD (Ishikawa et
al., 1999
).
Although CRY can entrain peripheral oscillators in the fly
tissue-autonomously (Emery et al.,
2000b), light input to the sLNvs can also occur through
retinal and extra-retinal photoreceptors
(Helfrich-Forster et al.,
2001
). As such, the sLNvs can still entrain in flies
that contain a single amino acid mutation that disrupts the flavin-binding
domain of CRY (cryb). Entrainment in these flies
to pulses of light is, however, impaired compared with the wildtype
(Stanewsky et al., 1998
).
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The mammalian central oscillator |
---|
As in Drosophila, mPER1 and mPER2 proteins undergo a substantial
phosphorylation-dependent delay in accumulation with respect to their mRNAs
(Akashi et al., 2002;
Lowrey et al., 2000
;
Takano et al., 2000
). mPER1
and mPER2 peak in concert with the mCRYs
(Table 1), form mPER-mCRY
complexes, and translocate to the nucleus
(Griffin et al., 1999
;
Kume et al., 1999
;
Vielhaber et al., 2001
;
Yagita et al., 2002
). mCRYs
(perhaps in conjunction with mPERs) then act as potent negative regulators by
directly interacting with the mCLK-BMAL1 heterodimer
(Griffin et al., 1999
;
Kume et al., 1999
;
Lee et al., 2001
). mPER2 has
also been shown to positively regulate Bmal1 transcription, similarly
to dPER positive regulation of dClk. However, mPER2-dependent
activation of Bmal1 is thought to occur indirectly via coactivation
or nuclear shuttling of an activator rather than inhibition of a repressor as
in the case of dClk (Shearman et
al., 2000
). This mechanistic difference explains why low levels of
Bmal1 transcript are seen in the SCN of mClk mutant mice:
activators and repressors of Bmal1 transcription are both dependent
on mCLK-BMAL1.
Light entrains the SCN by inducing transcription of mPer1 and
mPer2 (Albrecht et al.,
1997; Albrecht et al.,
2001
; Shearman et al.,
1997
; Shigeyoshi et al.,
1997
; Zylka et al.,
1998b
). Analysis of mCRYs in the SCN initially suggested that they
do not play a role in entrainment analogous to that of CRY in
Drosophila: the mPer genes are still activated in response
to light in mCry double-knockout mice
(Okamura et al., 1999
).
However, the mCrys were recently shown to be involved in entraining
the SCN to light (Selby et al.,
2000
; Thompson et al.,
2001
), but this role is carried out in the retina, where
opsin-based photoreceptors also function to entrain the SCN
(Berson et al., 2002
;
Freedman et al., 1999
;
Hattar et al., 2002
;
Provencio et al., 2002
).
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Mammalian peripheral oscillators |
---|
Recent in vivo studies in mouse liver have shown that mPER1 and mPER2 are
rate limiting for the nuclear translocation of mCRYs and, in the SCN, mPERs
require mCRYs to achieve and maintain nuclear translocation
(Shearman et al., 2000;
Vielhaber et al., 2001
;
Yagita et al., 2002
). The low
levels of Bmal1 mRNA in mCry-deficient mice and the
dependence of mPERs and mCRYs on each other for nuclear translocation suggest,
therefore, that nuclear mPER and/or mCRY is necessary for the positive
regulation of Bmal1. Whether it is nuclear mPER, mCRY or both, the
positive regulatory effect of these factors on Bmal1 transcription
(via relief of mCLK-BMAL1-dependent repression) ensures that the
mPers and Bmal1 cycle in anti-phase with one another
(Table 1).
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Functional divergence: TIMs and CRYs in flies and mice |
---|
A role for Drosophila CRY as an inhibitor of dCLK-CYC (analogous
to that of mCRY in inhibiting mCLK-BMAL1) has not been investigated. However,
in LD cycles, CRY starts to accumulate in the dark at a time when
per/tim transcription (by dCLK-CYC) first starts being repressed
(Table 1). Given the role of
mCRYs in the mammalian SCN, re-examination of previous results in the fly also
suggests that mCRY and dCRY are more functionally conserved than was
previously believed. For example, in Drosophila cell culture, CRY
nuclear localization is dependent on both PER and TIM (CRY and TIM alone are
insufficient) and appears to be induced by light
(Ceriani et al., 1999).
However, CRY-TIM interactions are also evident in the dark
(Ceriani et al., 1999
;
Rosato et al., 2001
). Further,
flies containing the cryb mutation have constitutive
intermediate levels of per and tim transcripts and PER and
TIM protein in whole heads (Stanewsky et
al., 1998
). In the photoreceptors of these mutants TIM protein,
and presumably PER and PER-TIM, remains predominantly cytoplasmic
(Stanewsky et al., 1998
).
These phenotypes (i.e. cytoplasmic TIM and intermediate levels of per
and tim mRNAs) precisely mimic those of per01
flies (Hunter-Ensor et al.,
1996
), which suggests that CRY and PER cooperatively translocate
to the nucleus in fly peripheral clocks. One caveat is that nuclear TIM, and
presumably PER, is present in the renal Malpighian tubules of
cryb mutants
(Ivanchenko et al., 2001
). It
will be interesting to see whether, as is the case for mPER in
mCry-deficient mice, such staining is actually peri-nuclear
(Shearman et al., 2000
).
In Drosophila peripheral oscillators CRY might therefore
facilitate PER-TIM nuclear translocation, or vice versa, just as mPERs and
mCRYs require each other for nuclear entry in mammals. Such a conserved role
is supported by the recent finding that dCRY can engage in protein-protein
interactions with dPER independently of TIM
(Rosato et al., 2001). Thus,
in addition to mediating PER nuclear localization in flies, TIM might also
facilitate movement of CRY into the nucleus. In mammals, mPERs and mCRYs have
bypassed this requirement for TIM, thus rendering TIM redundant. Hence,
although the roles of TIM in flies and mice have clearly diverged, the
functions of the PERs and CRYs might still have been largely retained in fly
and mouse peripheral tissues and the SCN, but not the sLNvs, where
CRY is not critical for oscillator function
(Emery et al., 2000a
;
Emery et al., 2000b
;
Stanewsky et al., 1998
).
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Transcript cycling of the positive factors: dClk and Bmal1 |
---|
So why is dClk rhythmically expressed in flies and Bmal1 rather than mClk rhythmically expressed in mammals? dClk and cyc are both bHLH-PAS-protein-encoding genes that presumably derived from a single common ancestor and were once under the same regulatory control. Thus, after activation, both genes would have been subject to dCLK-CYC-dependent repression. Since the cyclic accumulation of the dCLK-CYC dimer would require only one of these proteins to cycle, regulation of the other could be more flexible. Hence, elements concerned with cyc repression were lost, and the fly oscillator appears to have chosen cyclic regulation of dClk over cyc. Conversely, in mammals, Bmal1 was chosen over mClk, and so mClk regulation became more flexible. In support of this theory is the fact that in all mammalian clock tissues examined thus far, Bmal1 is always present and cycles at the mRNA level (Table 1). mClk and Npas2, by contrast, show variability in their spatial expression and cyclic nature. For instance, mClk expression in the SCN is constitutive, whereas Npas2 expression cycles in the vasculature (see Table 1 and below).
Do dClk and Npas2 share any similarities in their regulation? Recent in vivo work on the mouse vasculature has shown that Npas2 mRNA transcripts cycle. This suggests that, unlike its constitutively expressed analog mClk, Npas2 regulation is more like that of dClk. Bmal1 transcripts also cycle in the vasculature, peaking at the same time as those of Npas2 (Table 1). This observation is particularly interesting because it shows that the oscillatory phases of both positive elements in the mouse vasculature are more similar to those of the fly than to those of the mouse SCN.
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Phase relationships between central and peripheral oscillators |
---|
Cultured mammalian fibroblasts also contain a circadian clock that is set
by various pharmacological agents (e.g. serum shock, dexamethasone and
endothelin 1) thought to mimic endogenous humoral factors
(Balsalobre et al., 2000a;
Balsalobre et al., 1998
;
Yagita et al., 2001
). The
oscillator in these cells has properties similar to those of that in other
mammalian tissues: Per mRNA cycles in antiphase to Bmal1
mRNA; PER1 and PER2 accumulation is delayed compared with their peak mRNA
levels; clock gene expression can be entrained by SCN cells; and clock
function is dependent on Cry genes
(Allen et al., 2001
;
Balsalobre et al., 1998
;
Yagita et al., 2001
). The
oscillator mechanism in cultured fibroblasts is presumed to be like that in
other peripheral tissues, but regulation of the Bmal1 loop has not
been tested to determine whether this is the case. Moreover, the phase of
clock gene expression is expected to be similar to that in other peripheral
tissues, but it is difficult to assess the phase of expression relative to an
LD cycle since the clock is set by pharmacological agents.
Interestingly, peripheral oscillators in other vertebrates have phases
closer to the SCN than to peripheral tissues of mammals. In the
Xenopus eye, xPer1, xCry1, xCry2a and xCry2b mRNAs
peak at CT 18-02 hours (Zhu and
Green, 2001
; Zhuang et al.,
2000
) and Bmal1 peaks at CT 11-15 hours (C. Green,
personal communication). A similar situation exists in the chicken pineal
gland: cCry2 and cPer2 mRNAs peak at CT 22-02 hours and
cBal1 and cBmal2 mRNAs peak at CT 10-14 hours
(Bailey et al., 2002
;
Fukada and Okano, 2002
;
Yamamoto et al., 2001
).
Zebrafish peripheral oscillators (e.g. those in the liver, eye, pineal gland,
kidney and an embryonic cell line) are unusual because they are directly light
entrainable, as is the case with Drosophila oscillators, but phase
shifts are mediated by the light-induced expression of mPer2, as in
the mammalian SCN (Pando et al.,
2001
; Whitmore et al.,
2000
). The phase of zebrafish peripheral oscillators is similar to
those of Xenopus and chickens: zfPer1, zfPer2 and
zfPer3 peak at ZT 00-06 hours and zfClk, zfBmal1 and
zfBmal2 peak at ZT 12-18 hours
(Cermakian et al., 2000
;
Pando et al., 2001
;
Whitmore et al., 1998
). Thus,
in non-mammalian vertebrates, the phase of rhythmically expressed clock genes
in peripheral tissues is a few hours earlier than the mammalian SCN and almost
12 hours earlier than mammalian peripheral tissues. In each case, the rhythmic
repressors are essentially antiphase to the rhythmic activators, owing to the
interlocked feedback loop mechanism.
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mCRY verses dCRY revisited |
---|
Recent work has shown that, in the fly, CRY may serve both roles. In the
central oscillator it serves as the predominant photoreceptor but is
dispensable within the core clockwork: the cryb mutant has
wild-type free-running locomotor activity in constant light conditions that
render wild-type flies arrhythmic (Emery
et al., 2000a). In peripheral oscillators, however, CRY may well
serve as an integral clock component. Two key experiments have shown this. The
first relies on the fact that the circadian clock in flies can be entrained by
temperature cycles, thus, allowing the photoreceptive role of CRY to be
uncoupled from its oscillator function. When wild-type flies are entrained in
DD to temperature cycles and then transferred to constant temperature they
show clock-driven behavioral rhythms in locomotor activity (which are LN
dependent) and in electroantennogram (EAG) responses to odorant (an antennal
output that is thought to be driven by oscillator cells in the antennae)
(Krishnan et al., 2001
;
Wheeler et al., 1993
). When
the cryb mutant is treated similarly it retains a
functional sLNv oscillator but loses EAG rhythms, which shows that
the peripheral antennal clock is non-functional
(Krishnan et al., 2001
).
Importantly, loss of the EAG output rhythm in temperature-entrained
cryb flies results from a non-functional oscillator,
because rhythmic per and tim mRNA transcription in antennae
is severely crippled compared with that in temperature-entrained wild-type
flies (Krishnan et al., 2001
).
Although it remains possible that CRY is also a thermoreceptor, the most
parsimonious interpretation of this result is that the non-functional antennal
clock results from a dependence of the oscillator on CRY. The second
experiment focused on the renal Malpighian tubules (Mts) and the oscillating
nature of the clock proteins PER and TIM in this tissue. Ivanchenko et al.
showed that, in cryb flies, the oscillations of PER and
TIM in Mts are disrupted in LD conditions and abolished in DD, whereas PER/TIM
oscillations in the sLNvs are essentially wild-type in LD and DD
(Ivanchenko et al., 2001
).
Taken together, these data indicate that CRY is an essential component of the
oscillator in peripheral, but not central, clocks.
In mice, a similar problem of dissecting the role of mCRYs as
photoreceptors was encountered. Because mCRYs are a core component of the
oscillator, mCRY-double-knockout mice exhibit arrhythmic behavior (i.e. the
central oscillator is non-functional) (van
der Horst et al., 1999;
Vitaterna et al., 1999
). mCRYs
were not believed to have photoreceptive properties, because in the SCNs of
these mice, light pulses administered in vivo can induce transcription of core
clock genes: mPer1 and mPer2
(Okamura et al., 1999
). The
interpretation was that photic input to the oscillator can occur in the
absence of mCRYs. Freedman et al. and Selby et al., have shown that mice
lacking either classical opsin-based photoreceptors [retinal
degeneration (rd/rd) mutants missing rods and most cones] or
mCry1 and mCry2 can in fact entrain to LD cycles
(Freedman et al., 1999
;
Selby et al., 2000
). However,
mice lacking both photoreceptor types have severely impaired ability to
entrain, which indicates that opsin and mCRY have redundant roles in the
transduction of light information (Selby
et al., 2000
). Further support for mCRYs involvement in light
transduction comes from experiments eliminating opsin-based photoreception by
ocular retinaldehyde deprivation, which leaves photic signaling to the SCN
intact (Thompson et al.,
2001
). The discovery of another mammalian photoreceptor,
melanopsin, in retinal ganglion cells that project to the SCN also suggests
that, in common with the sLNvs in Drosophila, the SCN has
redundant mechanisms for entrainment
(Hattar et al., 2002
;
Provencio et al., 2002
).
These studies suggest that dCRY and mCRYs function similarly in flies and
mammals. In both, they serve as core clock components and/or as photoreceptors
depending on the tissue. A similar situation exists in zebrafish, but the six
zfCry genes in this species have become specialized, functioning as
either core clock components or as photoreceptors
(Cermakian et al., 2002;
Kobayashi et al., 2000
). Since
photoentrainment of zebrafish peripheral tissues is dependent on blue-light
photoreceptors, and therefore probably cryptochromes
(Cermakian et al., 2002
), it
will be interesting to determine how CRY photic signaling has evolved from a
TIM-degradation-based light entrainment mechanism in Drosophila to a
zfPer2-induction-based mechanism in zebrafish.
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Conclusions |
---|
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Acknowledgments |
---|
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Footnotes |
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References |
---|
Akashi, M., Tsuchiya, Y., Yoshino, T. and Nishida, E.
(2002). Control of intracellular dynamics of mammalian period
proteins by casein kinase I epsilon (CKIepsilon) and CKIdelta in cultured
cells. Mol. Cell. Biol.
22,1693
-1703.
Albrecht, U., Sun, Z. S., Eichele, G. and Lee, C. C. (1997). A differential response of two putative mammalian circadian regulators, mper1 and mper2, to light. Cell 91,1055 -1064.[Medline]
Albrecht, U., Zheng, B., Larkin, D., Sun, Z. S. and Lee, C.
C. (2001). mPer1 and mper2 are essential
for normal resetting of the circadian clock. J. Biol.
Rhythms 16,100
-104.
Allada, R., White, N. E., So, W. V., Hall, J. C. and Rosbash, M. (1998). A mutant Drosophila homolog of mammalian Clock disrupts circadian rhythms and transcription of period and timeless. Cell 93,791 -804.[Medline]
Allada, R., Emery, P., Takahashi, J. S. and Rosbash, M. (2001). Stopping time: the genetics of fly and mouse circadian clocks. Annu. Rev. Neurosci. 24,1091 -1119.[Medline]
Allen, G., Rappe, J., Earnest, D. J. and Cassone, V. M.
(2001). Oscillating on borrowed time: diffusible signals from
immortalized suprachiasmatic nucleus cells regulate circadian rhythmicity in
cultured fibroblasts. J. Neurosci.
21,7937
-7943.
Bae, K., Lee, C., Sidote, D., Chuang, K.-Y. and Edery, I.
(1998). Circadian regulation of a Drosophila homolog of
the mammalian Clock gene: PER and TIM function as positive
regulators. Mol. Cell. Biol.
18,6142
-6151.
Bae, K., Lee, C., Hardin, P. E. and Edery, I.
(2000). dCLOCK is present in limiting amounts and likely mediates
daily interactions between the dCLOCK-CYC transcription factor and the PER-TIM
complex. J. Neurosci.
20,1746
-1753.
Bae, K., Jin, X., Maywood, E. S., Hastings, M. H., Reppert, S. M. and Weaver, D. R. (2001). Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock. Neuron 30,525 -536.[Medline]
Bailey, M. J., Chong, N. W., Xiong, J. and Cassone, V. M. (2002). Chickens' Cry2: molecular analysis of an avian cryptochrome in retinal and pineal photoreceptors. FEBS Lett. 513,169 -174.[Medline]
Balsalobre, A., Damiola, F. and Schibler, U. (1998). A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93,929 -937.[Medline]
Balsalobre, A., Brown, S. A., Marcacci, L., Tronche, F.,
Kellendonk, C., Reichardt, H. M., Schutz, G. and Schibler, U.
(2000a). Resetting of circadian time in peripheral tissues by
glucocorticoid signaling. Science
289,2344
-2347.
Balsalobre, A., Marcacci, L. and Schibler, U. (2000b). Multiple signaling pathways elicit circadian gene expression in cultured Rat-1 fibroblasts. Curr. Biol. 10,1291 -1294.[Medline]
Berson, D. M., Dunn, F. A. and Takao, M.
(2002). Phototransduction by retinal ganglion cells that set the
circadian clock. Science
295,1070
-1073.
Brandes, C., Plautz, J. D., Stanewsky, R., Jamison, C. F., Straume, M., Wood, K. V., Kay, S. A. and Hall, J. C. (1996). Novel features of drosophila period Transcription revealed by real-time luciferase reporting. Neuron 16,687 -692.[Medline]
Bunger, M. K., Wilsbacher, L. D., Moran, S. M., Clendenin, C., Radcliffe, L. A., Hogenesch, J. B., Simon, M. C., Takahashi, J. S. and Bradfield, C. A. (2000). Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103,1009 -1017.[Medline]
Ceriani, M. F., Darlington, T. K., Staknis, D., Mas, P., Petti,
A. A., Weitz, C. J. and Kay, S. A. (1999). Light-dependent
sequestration of TIMELESS by CRYPTOCHROME. Science
285,553
-556.
Cermakian, N., Whitmore, D., Foulkes, N. S. and Sassone-Corsi,
P. (2000). Asynchronous oscillations of two zebrafish CLOCK
partners reveal differential clock control and function. Proc.
Natl. Acad. Sci. USA 97,4339
-4344.
Cermakian, N., Monaco, L., Pando, M. P., Dierich, A. and
Sassone-Corsi, P. (2001). Altered behavioral rhythms and
clock gene expression in mice with a targeted mutation in the Period1
gene. EMBO J. 20,3967
-3974.
Cermakian, N., Pando, M. P., Thompson, C. L., Pinchak, A. B., Selby, C. P., Gutierrez, L., Wells, D. E., Cahill, G. M., Sancar, A. and Sassone-Corsi, P. (2002). Light induction of a vertebrate clock gene involves signaling through blue-light receptors and MAP kinases. Curr. Biol. 12,844 -848.[Medline]
Cheng, M. Y., Bullock, C. M., Li, C., Lee, A. G., Bermak, J. C., Belluzzi, J., Weaver, D. R., Leslie, F. M. and Zhou, Q. Y. (2002). Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature 417,405 -410.[Medline]
Darlington, T. K., Wager-Smith, K., Ceriani, M. F., Staknis, D.,
Gekakis, N., Steeves, T. D. L., Weitz, C. J., Takahashi, J. S. and Kay, S.
A. (1998). Closing the circadian feedback loop: CLOCK induced
transcription of its own inhibitors, period and timeless.Science 280,1599
-1603.
Egan, E. S., Franklin, T. M., Hilderbrand-Chae, M. J., McNeil,
G. P., Roberts, M. A., Schroeder, A. J., Zhang, X. and Jackson, F. R.
(1999). An extraretinally expressed insect cryptochrome with
similarity to the blue light photoreceptors of mammals and plants.
J. Neurosci. 19,3665
-3673.
Emery, I. F., Noveral, J. M., Jamison, C. F. and Siwicki, K.
K. (1997). Rhythms of Drosophila period gene
expression in culture. Proc. Natl. Acad. Sci. USA
94,4092
-4096.
Emery, P., So, W. V., Kaneko, M., Hall, J. C. and Rosbash, M. (1998). CRY, a Drosophila clock and light-regulated cryptochrome, is a major contributor to circadian rhythm resetting and photosensitivity. Cell 95,669 -679.[Medline]
Emery, P., Stanewsky, R., Hall, J. C. and Rosbash, M. (2000a). A unique circadian-rhythm photoreceptor. Nature 404,456 -457.[Medline]
Emery, P., Stanewsky, R., Helfrich-Forster, C., Emery-Le, M., Hall, J. C. and Rosbash, M. (2000b). Drosophila CRY is a deep brain circadian photoreceptor. Neuron 26,493 -504.[Medline]
Ewer, J., Frisch, B., Hamblen-Coyle, M. J., Rosbash, M. and Hall, J. C. (1992). Expression of the period clock gene within different cell types in the brain of Drosophila adults and mosaic analysis of these cells' influence on circadian behavioral rhythms. J. Neurosci. 12,3321 -3349.[Abstract]
Field, M. D., Maywood, E. S., O'Brien, J. A., Weaver, D. R., Reppert, S. M. and Hastings, M. H. (2000). Analysis of clock proteins in mouse SCN demonstrates phylogenetic divergence of the circadian clockwork and resetting mechanisms. Neuron 25,437 -447.[Medline]
Freedman, M. S., Lucas, R. J., Soni, B., von Schantz, M., Munoz,
M., David-Gray, Z. and Foster, R. (1999). Regulation of
mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors.
Science 284,502
-504.
Frisch, B., Hardin, P. E., Hamblen-Coyle, M. J., Rosbash, M. R. and Hall, J. C. (1994). A promoterless period gene mediates behavioral rhythmicity and cyclical per expression in a restricted subset of the Drosophila nervous system. Neuron 12,555 -570.[Medline]
Fukada, Y. and Okano, K. (2002). Circadian clock system in then pineal gland. Mol. Neurobiol. 25, 19-30.[Medline]
Garcia, J. A., Zhang, D., Estill, S. J., Michnoff, C., Rutter,
J., Reick, M., Scott, K., Diaz-Arrastia, R. and McKnight, S. L.
(2000). Impaired cued and contextual memory in NPAS2-deficient
mice. Science 288,2226
-2230.
Gekakis, N., Saez, L., Delahaye-Brown, A. M., Myers, M. P., Sehgal, A., Young, M. W. and Weitz, C. J. (1995). Isolation of timeless by PER protein interaction: defective interaction between timeless protein and long-period mutant PERL. Science 270,811 -815.[Abstract]
Gekakis, N., Staknis, D., Nguyen, H. B., Davis, F. C.,
Wilsbacher, L. D., King, D. P., Takahashi, J. S. and Weitz, C. J.
(1998). Role of the CLOCK protein in the mammalian circadian
mechanism. Science 280,1564
-1569.
Giebultowicz, J. M. and Hege, D. M. (1997). Circadian clock in Malpighian tubules. Nature 386, 664.[Medline]
Glossop, N. R. J., Lyons, L. C. and Hardin, P. E.
(1999). Interlocked feedback loops within the Drosophila
circadian oscillator. Science
286,766
-768.
Griffin, E. A., Jr, Staknis, D. and Weitz, C. J.
(1999). Light-independent role of CRY1 and CRY2 in the mammalian
circadian clock. Science
286,768
-771.
Hao, H., Allen, D. L. and Hardin, P. E. (1997). A circadian enhancer mediates PER-dependent mRNA cycling in Drosophila.Mol. Cell. Biol. 17,3687 -3693.[Abstract]
Hardin, P. E., Hall, J. C. and Rosbash, M. (1990). Feedback of the Drosophila period gene product on circadian cycling of its messenger RNA levels. Nature 342,536 -540.
Hattar, S., Liao, H. W., Takao, M., Berson, D. M. and Yau, K.
W. (2002). Melanopsin-containing retinal ganglion cells:
architecture, projections, and intrinsic photosensitivity.
Science 295,1065
-1070.
Helfrich-Forster, C. (1996). Drosophila rhythms: from brain to behavior. Semin. Cell Dev. Biol. 7,791 -802.
Helfrich-Forster, C. (1998). Robust circadian rhythmicity of Drosophila melanogaster requires the presence of lateral neurons: a brain-behavioral study of disconnected mutants. J. Comp. Physiol. A 182,435 -453.[Medline]
Helfrich-Forster, C., Winter, C., Hofbauer, A., Hall, J. C. and Stanewsky, R. (2001). The circadian clock of fruit flies is blind after elimination of all known photoreceptors. Neuron 30,249 -261.[Medline]
Hogenesch, J. B., Gu, Y. Z., Jain, S. and Bradfield, C. A.
(1998). The basic-helix-loop-helix-PAS orphan MOP3 forms
transcriptionally active complexes with circadian and hypoxia factors.
Proc. Natl. Acad. Sci. USA
95,5474
-5479.
Hunter-Ensor, M., Ousley, A. and Sehgal, A. (1996). Regulation of the Drosophila protein Timeless suggests a mechanism for resetting the circadian clock by light. Cell 84,677 -685.[Medline]
Ishikawa, T., Matsumoto, A., Kato, T., Jr, Togashi, S., Ryo, H.,
Ikenaga, M., Todo, T., Ueda, R. and Tanimura, T. (1999). dCRY
is a Drosophila photoreceptor protein implicated in light entrainment
of circadian rhythm. Genes Cells
4, 57-65.
Ivanchenko, M., Stanewsky, R. and Giebultowicz, J. M.
(2001). Circadian photoreception in Drosophila:
functions of cryptochrome in peripheral and central clocks. J.
Biol. Rhythms 16,205
-215.
Jin, X., Shearman, L. P., Weaver, D. R., Zylka, M. J., de Vries, G. J. and Reppert, S. M. (1999). A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock. Cell 96,57 -68.[Medline]
Klein, D. C., Moore, R. Y. and Reppert, S. M. (eds) (1991). Suprachiasmatic Nucleus: The Mind's Clock. New York: Oxford University Press.
Kloss, B., Price, J. L., Saez, L., Blau, J., Rothenfluh, A., Wesley, C. S. and Young, M. W. (1998). The Drosophila clock gene double-time encodes a protein closely related to human casein kinase Iepsilon. Cell 94, 97-107.[Medline]
Kobayashi, Y., Ishikawa, T., Hirayama, J., Daiyasu, H., Kanai,
S., Toh, H., Fukuda, I., Tsujimura, T., Terada, N., Kamei, Y. et al.
(2000). Molecular analysis of zebrafish photolyase/cryptochrome
family: two types of cryptochromes present in zebrafish. Genes
Cells 5,725
-738.
Kramer, A., Yang, F. C., Snodgrass, P., Li, X., Scammell, T. E.,
Davis, F. C. and Weitz, C. J. (2001). Regulation of daily
locomotor activity and sleep by hypothalamic EGF receptor signaling.
Science 294,2511
-2515.
Krishnan, B., Levine, J. D., Lynch, M. K., Dowse, H. B., Funes, P., Hall, J. C., Hardin, P. E. and Dryer, S. E. (2001). A new role for cryptochrome in a Drosophila circadian oscillator. Nature 411,313 -317.[Medline]
Kume, K., Zylka, M. J., Sriram, S., Shearman, L. P., Weaver, D. R., Jin, X., Maywood, E. S., Hastings, M. H. and Reppert, S. M. (1999). mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 98,193 -205.[Medline]
Lee, C., Parikh, V., Itsukaichi, T., Bae, K. and Edery, I. (1996). Resetting the Drosophila clock by photic regulation of PER and a PER-TIM complex. Science 271,1740 -1744.[Abstract]
Lee, C., Bae, K. and Edery, I. (1999). PER and
TIM inhibit the DNA binding activity of a dCLOCK-CYC/dBMAL1 heterodimer
without disrupting formation of the heterodimer: A basis for circadian
transcription. Mol. Cell. Biol.
19,5316
-5325.
Lee, C., Etchegaray, J. P., Cagampang, F. R., Loudon, A. S. and Reppert, S. M. (2001). Posttranslational mechanisms regulate the mammalian circadian clock. Cell 107,855 -867.[Medline]
Lowrey, P. L., Shimomura, K., Antoch, M. P., Yamazaki, S.,
Zemenides, P. D., Ralph, M. R., Menaker, M. and Takahashi, J. S.
(2000). Positional syntenic cloning and functional
characterization of the mammalian circadian mutation tau.Science 288,483
-492.
Martinek, S., Inonog, S., Manoukian, A. S. and Young, M. W. (2001). A role for the segment polarity gene shaggy/GSK-3 in the Drosophila circadian clock. Cell 105,769 -779.[Medline]
McNamara, P., Seo, S. P., Rudic, R. D., Sehgal, A., Chakravarti, D. and FitzGerald, G. A. (2001). Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: a humoral mechanism to reset a peripheral clock. Cell 105,877 -889.[Medline]
Meyer-Bernstein, E. L. and Sehgal, A. (2001).
Molecular regulation of circadian rhythms in Drosophila and mammals.
Neuroscientist 7,496
-505.
Miyamoto, Y. and Sancar, A. (1999). Circadian regulation of cryptochrome genes in the mouse. Brain Res. Mol. Brain Res. 71,238 -243.[Medline]
Moore, R. Y., Speh, J. C. and Card, J. P. (1995). The retinohypothalamic tract originates from a distinct subdivision of retinal ganglion cells. J. Comp. Neurol. 352,351 -366.[Medline]
Myers, M. P., Wager-Smith, K., Rothenfluh-Hilfiker, A. and Young, M. W. (1996). Light-induced degradation of TIMELESS and entrainment of the Drosophila circadian clock. Science 271,1736 -1740.[Abstract]
Oishi, K., Sakamoto, K., Okada, T., Nagase, T. and Ishida, N. (1998). Humoral signals mediate the circadian expression of rat period homologue (rPer2) mRNA in peripheral tissues. Neurosci. Lett. 256,117 -119.[Medline]
Oishi, K., Fukui, H. and Ishida, N. (2000). Rhythmic expression of BMAL1 mRNA is altered in Clock mutant mice: differential regulation in the suprachiasmatic nucleus and peripheral tissues. Biochem. Biophys. Res. Commun. 268,164 -171.[Medline]
Okamura, H., Miyake, S., Sumi, Y., Yamaguchi, S., Yasui, A.,
Muijtjens, M., Hoeijmakers, J. H. and van der Horst, G. T.
(1999). Photic induction of mPer1 and mPer2 in
cry-deficient mice lacking a biological clock.
Science 286,2531
-2534.
Pando, M. P., Pinchak, A. B., Cermakian, N. and Sassone-Corsi,
P. (2001). A cell-based system that recapitulates the dynamic
light-dependent regulation of the vertebrate clock. Proc. Natl.
Acad. Sci. USA 98,10178
-10183.
Plautz, J. D., Kaneko, M., Hall, J. C. and Kay, S. A.
(1997). Independent photoreceptive circadian clocks throughout
Drosophila. Science 278,1632
-1635.
Price, J. L., Blau, J., Rothenfluh, A., Abodeely, M., Kloss, B. and Young, M. W. (1998). double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation. Cell 94,83 -95.[Medline]
Provencio, I., Rollag, M. D. and Castrucci, A. M. (2002). Photoreceptive net in the mammalian retina. This mesh of cells may explain how some blind mice can still tell day from night. Nature 415,493 .
Reick, M., Garcia, J. A., Dudley, C. and McKnight, S. L.
(2001). NPAS2: an analog of clock operative in the mammalian
forebrain. Science 293,506
-509.
Rosato, E., Codd, V., Mazzotta, G., Piccin, A., Zordan, M., Costa, R. and Kyriacou, C. P. (2001). Light-dependent interaction between Drosophila CRY and the clock protein PER mediated by the carboxy terminus of CRY. Curr. Biol. 11,909 -917.[Medline]
Rutila, J. E., Suri, V., Le, M., So, W. V., Rosbash, M. and Hall, J. C. (1998). CYCLE is a second bHLH-PAS clock protein essential for circadian rhythmicity and transcription of Drosophila period and timeless. Cell 93,805 -814.[Medline]
Saez, L. and Young, M. W. (1996). Regulation of nuclear entry of the Drosophila clock proteins period and timeless. Neuron 17,911 -920.[Medline]
Sauman, I. and Reppert, S. M. (1996). Circadian clock neurons in the silkmoth Antheraea pernyi: novel mechanisms of Period protein regulation. Neuron 17,889 -900.[Medline]
Saunders, D. S., Gillanders, S. W. and Lewis, R. D. (1994). Light-pulse phase response curves for the locomotor activity rhythm in period mutants of Drosophila melanogaster.J. Insect Physiol. 40,957 -968.
Selby, C. P., Thompson, C., Schmitz, T. M., van Gelder, R. N.
and Sancar, A. (2000). Functional redundancy of cryptochromes
and classical photoreceptors for nonvisual ocular photoreception in mice.
Proc. Natl. Acad. Sci. USA
97,14697
-14702.
Shearman, L. P., Zylka, M. J., Weaver, D. R., Kolakowski, L. F., Jr and Reppert, S. M. (1997). Two period homologs: circadian expression and photic regulation in the suprachiasmatic nuclei. Neuron 19,1261 -1269.[Medline]
Shearman, L. P., Sriram, S., Weaver, D. R., Maywood, E. S.,
Chaves, I., Zheng, B., Kume, K., Lee, C. C., van der Horst, G. T., Hastings,
M. H. et al. (2000). Interacting molecular loops in the
mammalian circadian clock. Science
288,1013
-1019.
Shigeyoshi, Y., Taguchi, K., Yamamoto, S., Takekida, S., Yan, L., Tei, H., Moriya, T., Shibata, S., Loros, J. J., Dunlap, J. C. et al. (1997). Light-induced resetting of a mammalian circadian clock is associated with rapid induction of the mPer1 transcript. Cell 91,1043 -1053.[Medline]
Stanewsky, R., Kaneko, M., Emery, P., Beretta, B., Wager-Smith, K., Kay, S. A., Rosbash, M. and Hall, J. C. (1998). The cryb mutation identifies cryptochrome as a circadian photoreceptor in Drosophila. Cell 95,681 -692.[Medline]
Takano, A., Shimizu, K., Kani, S., Buijs, R. M., Okada, M. and Nagai, K. (2000). Cloning and characterization of rat casein kinase 1epsilon. FEBS Lett. 477,106 -112.[Medline]
Thompson, C. L., Blaner, W. S., van Gelder, R. N., Lai, K.,
Quadro, L., Colantuoni, V., Gottesman, M. E. and Sancar, A.
(2001). Preservation of light signaling to the suprachiasmatic
nucleus in vitamin A-deficient mice. Proc. Natl. Acad. Sci.
USA 98,11708
-11713.
Ueyama, T., Krout, K. E., Nguyen, X. V., Karpitskiy, V., Kollert, A., Mettenleiter, T. C. and Loewy, A. D. (1999). Suprachiasmatic nucleus: a central autonomic clock. Nat. Neurosci. 2,1051 -1053.[Medline]
van der Horst, G. T., Muijtjens, M., Kobayashi, K., Takano, R., Kanno, S., Takao, M., de Wit, J., Verkerk, A., Eker, A. P., van Leenen, D. et al. (1999). Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398,627 -630.[Medline]
Vielhaber, E. L., Duricka, D., Ullman, K. S. and Virshup, D.
M. (2001). Nuclear export of mammalian PERIOD proteins.
J. Biol. Chem. 276,45921
-45927.
Vitaterna, M. H., Selby, C. P., Todo, T., Niwa, H., Thompson,
C., Fruechte, E. M., Hitomi, K., Thresher, R. J., Ishikawa, T., Miyazaki, J.
et al. (1999). Differential regulation of mammalian period
genes and circadian rhythmicity by cryptochromes 1 and 2. Proc.
Natl. Acad. Sci. USA 96,12114
-12119.
Vosshall, L. B., Price, J. L., Sehgal, A., Saez, L. and Young, M. W. (1994). Block in nuclear localization of period protein by a second clock mutation, timeless. Science 263,1606 -1609.[Medline]
Wang, G. K., Ousley, A., Darlington, T. K., Chen, D., Chen, Y., Fu, W., Hickman, L. J., Kay, S. A. and Sehgal, A. (2001). Regulation of the cycling of timeless (tim) RNA. J. Neurobiol. 47,161 -175.[Medline]
Wheeler, D. A., Hamblen-Coyle, M. J., Dushay, M. S. and Hall, J. C. (1993). Behavior in light-dark cycles of Drosophila mutants that are arrhythmic, blind or both. J. Biol. Rhythms 8,67 -94.[Medline]
Whitmore, D., Foulkes, N. S., Strahle, U. and Sassone-Corsi, P. (1998). Zebrafish Clock rhythmic expression reveals independent peripheral circadian oscillators. Nat. Neurosci. 1,701 -707.[Medline]
Whitmore, D., Foulkes, N. S. and Sassone-Corsi, P. (2000). Light acts directly on organs and cells in culture to set the vertebrate circadian clock. Nature 404, 87-91.[Medline]
Yagita, K., Tamanini, F., van der Horst, G. T. and Okamura,
H. (2001). Molecular mechanisms of the biological clock in
cultured fibroblasts. Science
292,278
-281.
Yagita, K., Tamanini, F., Yasuda, M., Hoeijmakers, J. H., van
der Horst, G. T. and Okamura, H. (2002). Nucleocytoplasmic
shuttling and mCRY-dependent inhibition of ubiquitylation of the mPER2 clock
protein. EMBO J. 21,1301
-1314.
Yamamoto, K., Okano, T. and Fukada, Y. (2001). Chicken pineal Cry genes: light-dependent up-regulation of cCry1 and cCry2 transcripts. Neurosci. Lett. 313,13 -16.[Medline]
Yamazaki, S., Numano, R., Abe, M., Hida, A., Takahashi, R.,
Ueda, M., Block, G. D., Sakaki, Y., Menaker, M. and Tei, H.
(2000). Resetting central and peripheral circadian oscillators in
transgenic rats. Science
288,682
-685.
Young, M. W. and Kay, S. A. (2001). Time zones: a comparative genetics of circadian clocks. Nat. Rev. Genet. 2,702 -715.[Medline]
Young, M. E., Razeghi, P. and Taegtmeyer, H.
(2001). Clock genes in the heart: characterization and
attenuation with hypertrophy. Circ. Res.
88,1142
-1150.
Yu, W., Nomura, M. and Ikeda, M. (2002). Interactivating feedback loops within the mammalian clock: BMAL1 is negatively autoregulated and upregulated by CRY1, CRY2, and PER2. Biochem. Biophys. Res. Commun. 290,933 -941.[Medline]
Zeng, H., Qian, Z., Myers, M. P. and Rosbash, M. (1996). A light-entrainment mechanism for the Drosophila circadian clock. Nature 380,129 -135.[Medline]
Zerr, D. M., Hall, J. C., Rosbash, M. and Siwicki, K. K. (1990). Circadian fluctuations of period protein immunoreactivity in the CNS and the visual system of Drosophila. J. Neurosci. 10,2749 -2762.[Abstract]
Zheng, B., Albrecht, U., Kaasik, K., Sage, M., Lu, W., Vaishnav, S., Li, Q., Sun, Z. S., Eichele, G., Bradley, A. et al. (2001). Nonredundant roles of the mPer1 and mPer2 genes in the mammalian circadian clock. Cell 105,683 -694.[Medline]
Zhou, Y. D., Barnard, M., Tian, H., Li, X., Ring, H. Z.,
Francke, U., Shelton, J., Richardson, J., Russell, D. W. and McKnight, S.
L. (1997). Molecular characterization of two mammalian
bHLH-PAS domain proteins selectively expressed in the central nervous system.
Proc. Natl. Acad. Sci. USA
94,713
-718.
Zhu, H. and Green, C. B. (2001). Three cryptochromes are rhythmically expressed in Xenopus laevis retinal photoreceptors. Mol. Vis. 7, 210-215.[Medline]
Zhuang, M., Wang, Y., Steenhard, B. M. and Besharse, J. C. (2000). Differential regulation of two period genes in the Xenopus eye. Brain Res. Mol. Brain Res. 82, 52-64.[Medline]
Zylka, M. J., Shearman, L. P., Levine, J. D., Jin, X., Weaver, D. R. and Reppert, S. M. (1998a). Molecular analysis of mammalian timeless. Neuron 21,1115 -1122.[Medline]
Zylka, M. J., Shearman, L. P., Weaver, D. R. and Reppert, S. M. (1998b). Three period homologs in mammals: differential light responses in the suprachiasmatic circadian clock and oscillating transcripts outside of brain. Neuron 20,1103 -1110.[Medline]
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