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3 - Mammalian Circadian Bio, Lowrey & Takahashi.doc

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David Rollo

Article 3: Summary for mammalian circadian biology: elucidating genome-wide levels of temperal organization. • Circadian system – 1. SCN – in hypothalamus—entrained by daily light / dark cycle, 2. Transmit synchronizing signal to local circadian oscillates in peripheral tissue. • Biology clock/circadian rhythm – found in eukarya and bacteria, and some members of archaea. • Why need clock? – ie. cyanobacteria—oxygenic photosynthesis and nitrogen fixation—need to be separated either temporally or spatially. • a timing system, which regardless of environmental pressures, can create an internal biological day synchronized to the external world enables an organism to predict and prepare for daily environmental fluctuations • Konopka and Benzer – molecular mechanism of the circadian clock consists of a set of core clock genes and their protein products • Orthologous—relate to the ancestor—some organism that diverged from a common ancestor million yrs ago—many circadian clock genes are orthologous. Overview of the mammalian circadian system • 3 major components of circadian systems: o Light input pathway to a self sustained master circadian packemaker– circadian pacemaker  ganglion cell containing photo pigment, melanopsin  rod-cone system + melanopsin-containing ganglion cells— serve visual function and entrainment of the circadian system  photic information to retina to hypothalamus via RHT(retinalhypothalimic tract) to SCN (location of master circadian pacemaker, located in the anterior hypothalamus) o the circadian pacemaker  SCN contains about 8000-10000 neurons, which maintain circadian cycle detached from SCN  SCN neurons express synchronized circadian rhythms of spontaneous electrical activity, calcium oscillations, humoral ouptput, metabolic activity, and gene expression o output pathways by which the circadian pacemaker regulates overt rhythms in biochemistry, physiology and behaviour throughout the organisms  light enters SCN neural and hormonal out put signals that influence various rhythms in the body  SCN regulates sleep/wake via intrahypothalamic projections  SCN signals impringe onANS TGFa and prokineticin surpresses locomotor activity Cicadian phenotypes: Wheel running locomotor activity • Zeitgeber times (ZT) (time giver) == any daily environmental cure to which – circadian sysmter can synchronize and entrain.—i.e. light, may also be temperature and social cue. • When light deprived: Light pulse at – o early night -maximum phase delay o late night - maximum phase advanced o at day - small phase shift or none at all The Mammalian core oscillatory mechanism • core circadian clock genes code for proteins which form the primary molecular circadian oscillatory mechanism • Common feature of different species—participation of core clock gene in interconnected positive /negative auto regulatory feed back loops of transcription + translation. • circadian rhythms are genetically based arising from cycles of transcription, translation, protein-protein interaction, phosphorylation, nuclear translocation, and protein degradation all impose delays at various times every day to created coordinated 24h cycle • Mammal – two core clock gene—1. Clock (express in SCN constitutively), 2. Bmal1—peaks at middle of night. • Clock/Bmal1 heterodimerize (CLOCK:BMAL1 cis or M34) – activate transcription at E-box cis-regulatory enhancer sequence. • Clock/Bmal1 complex—activate core gene 1. Per—PAS protein family (Per1, 2, 3), 2. Cry – photoreceptor/photolyse family (Cry 1, 2)– peak as opposite as Bmal1 peak so mid to late day since BMAL1 is peak during mid circadian night • Core clock gene – after delayed by transcription—Per/Cry complex—go to nucleus—stop Clock/Bmal complex—lower Per/Cry level directly—mainly cause by Cry. • Positive feedback – daily transcriptional activity of CLOCK:BMAL1 • Negative feedback – stopping CLOCK:BMAL1 transcription by CRYs to inhibit their own transcription • Rev-erbα—activated by Clock/Bmal1 complex—acting on E-box enhacer. • Rev-erbaα—1. Indirectly inhibit own transcription by repressing at least one of its activator Bmal1, by puttinn RORES in its promoter sequence, whereas CRYAND PER associate with CLOCKAND BMAL directly, 2. Also inhibited by repression of Cry/per complex on CLOCK: BMAL1. • Inhibition of Rev-erba== timed circadian nuclear accumulation of Clock/Bmal1—mainly Bmal1 dependent—activation of Bmal1 depend on mPer2. • Phosphorylation of core circadian protein—function degradation – regulated by casein kinase I epsilon (CKIE)—thus form 24-hr rhythms of RNA/protein level. Mutations in Mammalian Core Clock Genes • Clock gene mutation lengthens the circadian period • BmalI/Mop3 mutation causes complete loss of circadian rhythmicity in dark • of Per y • Mutant Cry—1. Cry1 null mutant – 1 hr shorter , 2. Cry2 mutant – 1 hr longer, 3. lose both—arrythmicity. • Mutant Per—double mutant of Per1/Per2—strong circadian phenotype—if only Per3—slight shorten circadian period— may play a role in clock output • Syrian hamster tau mutation—in the gene coding CKIE?—1 mammal single gene circadian mutation—result of C-T transition—proof—1. SCN master circadian pacemaker, 2.Adiffusible signal can drive circadian rhythms in animal, 3. SCN-independent circadian oscillator exists in mammal retina. • Rev-erbα knockout—shorten free-running behavioral rhythms Time now for Timeless? • TIM/PER in Drosophila fly—same as CRY/PER complex in mammal – translocate to nucleus inhibit
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