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4 - Rhythmic Gene expression, Gall, C..doc

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McMaster University
David Rollo

Article 4 Rhythmic gene expression in pituitary depends in herterologous sensitization by the neurohormone melatonin Abstract -mammalian daily cycles are driven by a circadian clock -clock is based on the cell-autonomous rhythmic expression of clock genes -cycling expression of Period 1 (a clock gene) in the pituatory gland depends on heterologous sensitization of the adenosine A2beceptor -this happens by the nighttime activation of the melatonin mt1 receptors -eliminating melatonin suppresses the expression of Period 1 and increases the release of prolactin from the pituitary Introduction -if gene expression in not temporally correct, cellular malfunction and disease can result -hypothalamic suprachiasmatic nucleus (SCN): -partitions metabolic functions in 24 hour cycle -24 hour rhythm is regulated by transcription/translation feedback loops -PERIOD in humans in a transcription/translation feedback loop -PERIPHERAL RHYTHMS: -circadian rhythms are not limited to the cells of the SCN, they can be found in many tissues, but with a delayed timing with respect to the SCN -peripheral rhythms dampen in vitro after a few cycles b/c they depend on neuronal and/or neuroendocrine signals from the SCN -when the SCN and peripheral clock-controlled genes are not in synch, jet-lag and shift-work pathologies result -both neural and endocrine pathways can maintain circadian gene expression in the periphery: -Period (Per) gene rhythms can be regulated by glucocorticoids and cycles of restricted feeding in rodents -in rodent pineal gland: Per1 activity is sustained by noradrenergic activation of the cyclic AMP pathway -CYCLIC AMP PATHWAY: -sustains rodent Per1 activity -drives synthesis of pineal melatonin (which has neuroendocrine role in central circadian clock) -major coordinator of circadian and seasonal physiology -HYPOPHYSEAL PARS TUBERALIS (PT): -contains high density of receptors for melatonin -implicated in expression of both circadian rhythm and seasonal endocrine cycles -has clock genes with rhythms that are sensitive to time of day, and time of year -melatonin is an important link between the central circadian pacemaker (SCN?) and the PT (results in long-term modulation of prolactin levels) Results -used: wild-type C3H/HeN mice -levels of mPer1 (mRNA)sharply peaked in the PT just after dark-light transition -6 hours later: there was an increase in nuclear concentrations of mPER1 protein -these rhythms are generated by circadian rhythms (not the light-dark cycle b/c mPer1 (mRNA) and mPER1 rhythms were obvious in the PT under constant darkness) -PINEAL GLAND: -the pineal gland is the link b/w the SCN and PT -melatonin acts on the PT through its mt1R receptor -in mice without pineal glands (PinX) , both mPer1 (mRNA) and mPER1 expression was always high at all time points (no cycling) -prolonged absence of melatonin means that mice are no longer sensitive to the hormone in the PT) -/- -DELETION IN MELATONIN mt1 RECEPTOR (mtR ): -mPER1 was consistently low in the PT -this is tissue specific b/c the circadian expression of mPer1 and mPER1 in the
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