Nuclear receptors and circadian rhythms

1
Nuclear receptors and circadian rhythms

• Franck Delaunay
• Université de Nice-Sophia Antipolis

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Circadian rhythms
Bioluminescence
Photosynthesis
Hatching Locomotor activity
Sleep-wake cycle Body temperature Hormonal
secretionMetabolism Liver regeneration
3
Melatonin secretion in healthy humans
(10 male subjects)
300
250
200
150
of mean level
100
50
0
12
16
20
0
4
8
ZT time (h)
4
Rest-activity cycles in rodents
Zeitgeber time
Entrained (LD 1212)
Free-running (DD)
Circadian time
5
The three components modelfor circadian
clocks
Intput pathways(Zeitgeber)
Circadian oscillator
Output pathways
Clock-dependent physiology and behavior
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The genetic basis of circadian clocks
Adapted from Takahashi et al.
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A simplistic model of the mammalian circadian
oscillator
Synchronisers
cytoplasm
nucleus
Bmal1
Clock
Per1, Per2
CACGTG
Cry1, Cry2
CACGTG
Output signals
8
Where is located the circadian clock ?
CT10
CT22
9
Circadian clocks in peripheral tissues
Liver
Stra13
Liver
Heart
15
20
Liver
36B4
15
10
Per2
Heart
Stra13 / 36B4
10
Stra13
5
Per3
5
36B4
Clock
0
0
CT12
CT4
CT12
CT4
Kidney
Bmal1
Stra13
Kidney
Lung
30
25
36B4
36B4
25
20
20
Lung
15
15
Stra13 / 36B4
Stra13
10
10
5
5
36B4
0
0
Y
0
8
4
12
20
16
CT12
CT4
CT12
CT4
Circadian time
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Circadian gene expression is extensive in
peripheral organs
Delaunay Laudet, 2002
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Circadian gene expression is highly
tissue-specific
liver
SCN
liver
heart
37
462
575
21-28
335-380
80-337
Storch et al. 2002
Panda et al. Ueda et al. 2002
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Clock-dependent pathology
Circadian system
jetlag
FASPS
Centraloscillator
cardiovascularpathologies
Internal synchronizers
Autonomic, endocrine, behavioural and
food-related cues
Localoscillators
aging
cancer ?
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Intput pathways(Zeitgeber)
NRs
Circadian oscillator
Output pathways
Clock-dependent physiology and behavior
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Circadian expression of Rev-erba in Serum shocked
3Y1 rat fibroblasts
Rev-erba
36B4
time (h)
50 serum
0 serum
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Rev-erba P1 and P2 promoterscontain E-box
elements
P1
P2
Human
E1A
E1B
E2
1
5
,
1
5
8
Rat
E1A
E2
E1B
1
4
,
2
8
4
1
4
5
2
3
A
P
1
T
G
A
C
T
C
A
C
E

B
O
X



C
A
C
G
T
G
A
/
T

r
i
c
h

A
G
G
T
C
A
R
E
V
R
E
E

B
O
X



C
A
C
A
T
G
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(No Transcript)
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Rev-erba promoters are activatedby CLOCKBMAL1
and inhibited by CRY1
contrôle
Clock/Bmal1
Clock/Bmal1 bgal
Clock/Bmal1 Cry
0
1
2
3
0
2
4
6
P1
P2
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CLOCKBMAL1 binds to Rev-erbaP1 and P2 promoters
.
CLOCKBMAL1
C
B
m
P
e
r
1
m
P
e
r
1

R
e
v
1
R
e
v
2
R
e
v
3
R
e
v
5
R
e
v
3

4
R
e
v
4
(
D
N
A

c
o
m
p
e
t
i
t
o
r
)
1
0
0
1
0
0
1
0
0
1
0
0
1
0
0

1
0
0
1
0
0
1
0
0
1
0
1
0
1
0
1
0
1
0
1
0
1
0
1
0
(
M
o
l
a
r

e
x
c
e
s
s
)
E-box
m
P
e
r
1

p
r
o
b
e
19
Alteration of Rev-erba expression in Clock mutant
mice
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Bmal1 is a target of Rev-erba in vivo
From Preitner et al , Cell 2004
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Circadian expression of Rev-erba during Zebrafish
development
zebrafish
mammals
post-natal
embryonic
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Expression of Rev-erba in zebrafish epiphysis
48 hpf
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Expression of Rev-erba in zebrafish epiphysis and
retina
72 hpf
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Expression of Rev-erba in zebrafishepiphysis,
retina and optic tectum
96 hpf
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(No Transcript)
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The mammalian circadian oscillator
Synchronisers
nucleus
cytoplasm
Bmal1
Clock
Rev-erba
RORa
Per1, Per2
?
Cry1, Cry2
Output signals
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GR is required for dexamethasoneinduced
resetting of peripheral clocks
Balsalobre et al., 2000 Science
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Retinoic acid can reset the vascular clock
McNamara et al, Cell 2001
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Circadian expression of the Osteopontin gene in
bone is mediated by ERRa
Bone
Liver
3.0
2.5
2.0
1.5
Relative expression
1.0
0.5
0
ct (hr)
5
Opn
4
3
Relative expression
2
1
0
zt (hr)
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Alas1 is a target of the two circadian regulators
Stra13 and CARb in liver
Alas1
2.5
2.0
STRA13
1.5
Alas1/36B4
1.0
Alas1
CARb
0.5
0.0
0
8
4
12
20
16
Circadian time
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NRs are key regulators of circadian clocks
GR RARa RXRa Others ?
Intput pathways(Zeitgeber)
Rev-erba Rev-erbb RORa RORg
Circadian oscillator
ERRaCARb PPARa Rev-erbs ?RORs ?
Output pathways
Clock-dependent physiology and behavior