Organ-specific development characterizes circadian clock gene Per2 expression in rats

2014 ◽  
Vol 306 (1) ◽  
pp. R67-R74 ◽  
Author(s):  
Shin-ya Nishide ◽  
Kazuaki Hashimoto ◽  
Takuya Nishio ◽  
Ken-ichi Honma ◽  
Sato Honma
Keyword(s):  
Circadian Rhythms ◽  
Clock Gene ◽  
Developmental Stages ◽  
Phase Relationship ◽  
Developmental Changes ◽  
Circadian Phase ◽  
Peripheral Oscillators ◽  
Clock Gene Expression ◽  
Organ Specific

To explore developmental changes in circadian organization of central and peripheral oscillators, circadian rhythms in clock gene expression were examined in 12 organs in transgenic rats carrying a bioluminescence reporter for Per2. Organ slices were obtained from different developmental stages starting at postnatal day 5 and tissue was cultured for more than 6 days. In addition, four organs were examined from embryonic day 20. Robust circadian rhythms in bioluminescence were detected in all organs examined. The circadian period in vitro was specific to each organ and remained essentially the same during development. The circadian peak phase on the first day of culture was significantly different not only among organs but also in the same organ. Three patterns in circadian phase were detected during development. Thus, during development, circadian phase did not change in the suprachiasmatic nucleus, adrenal gland, and liver, whereas delay shifts were seen in the pineal, lung, heart, kidney, spleen, thymus, and testis. Finally, circadian phase advanced at postnatal day 10–15 and subsequently delayed in skeletal muscle and stomach.Circadian amplitude also showed developmental changes in several organs. These findings indicate that the temporal orders of physiological functions of various organs change during development. Such age-dependent and organ-specific changes in the phase relationship among circadian clocks most likely reflect entrainment to organ-specific time cues at different developmental stages.

scholarly journals Clock Gene Expression in Adult Primate Suprachiasmatic Nuclei and Adrenal: Is the Adrenal a Peripheral Clock Responsive to Melatonin?

Endocrinology ◽  
2008 ◽  
Vol 149 (4) ◽  
pp. 1454-1461 ◽  
Author(s):  
F. J. Valenzuela ◽  
C. Torres-Farfan ◽  
H. G. Richter ◽  
N. Mendez ◽  
C. Campino ◽  
...  
Keyword(s):  
Adrenal Gland ◽  
Clock Gene ◽  
Clock Genes ◽  
Phase Relationship ◽  
Suprachiasmatic Nuclei ◽  
Rhythmic Expression ◽  
Peripheral Oscillators ◽  
Clock Gene Expression ◽  
Timing System ◽  
Circadian Timing System

The circadian production of glucocorticoids involves the concerted action of several factors that eventually allow an adequate adaptation to the environment. Circadian rhythms are controlled by the circadian timing system that comprises peripheral oscillators and a central rhythm generator located in the suprachiasmatic nucleus (SCN) of the hypothalamus, driven by the self-regulatory interaction of a set of proteins encoded by genes named clock genes. Here we describe the phase relationship between the SCN and adrenal gland for the expression of selected core clock transcripts (Per-2, Bmal-1) in the adult capuchin monkey, a New World, diurnal nonhuman primate. In the SCN we found a higher expression of Bmal-1 during the h of darkness (2000–0200 h) and Per-2 during daytime h (1400 h). The adrenal gland expressed clock genes in oscillatory fashion, with higher values for Bmal-1 during the day (1400–2000 h), whereas Per-2 was higher at nighttime (about 0200 h), resulting in a 9- to 12-h antiphase pattern. In the adrenal gland, the oscillation of clock genes was accompanied by rhythmic expression of a functional output, the steroidogenic enzyme 3β-hydroxysteroid dehydrogenase. Furthermore, we show that adrenal explants maintained oscillatory expression of Per-2 and Bmal-1 for at least 36 h in culture. The acrophase of both transcripts, but not its overall expression along the incubation, was blunted by 100 nm melatonin. Altogether, these results demonstrate oscillation of clock genes in the SCN and adrenal gland of a diurnal primate and support an oscillation of clock genes in the adrenal gland that may be modulated by the neurohormone melatonin.

scholarly journals Development of diabetes does not alter behavioral and molecular circadian rhythms in a transgenic rat model of type 2 diabetes mellitus

2017 ◽  
Vol 313 (2) ◽  
pp. E213-E221 ◽  
Author(s):  
Jingyi Qian ◽  
Anthony P. Thomas ◽  
Analyne M. Schroeder ◽  
Kuntol Rakshit ◽  
Christopher S. Colwell ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Circadian Clock ◽  
Rat Model ◽  
Clock Gene ◽  
Transgenic Rat ◽  
Circadian Activity ◽  
Melatonin Secretion ◽  
Clock Gene Expression

Metabolic state and circadian clock function exhibit a complex bidirectional relationship. Circadian disruption increases propensity for metabolic dysfunction, whereas common metabolic disorders such as obesity and type 2 diabetes (T2DM) are associated with impaired circadian rhythms. Specifically, alterations in glucose availability and glucose metabolism have been shown to modulate clock gene expression and function in vitro; however, to date, it is unknown whether development of diabetes imparts deleterious effects on the suprachiasmatic nucleus (SCN) circadian clock and SCN-driven outputs in vivo. To address this question, we undertook studies in aged diabetic rats transgenic for human islet amyloid polypeptide, an established nonobese model of T2DM (HIP rat), which develops metabolic defects closely recapitulating those present in patients with T2DM. HIP rats were also cross-bred with a clock gene reporter rat model (Per1:luciferase transgenic rat) to permit assessment of the SCN and the peripheral molecular clock function ex vivo. Utilizing these animal models, we examined effects of diabetes on 1) behavioral circadian rhythms, 2) photic entrainment of circadian activity, 3) SCN and peripheral tissue molecular clock function, and 4) melatonin secretion. We report that circadian activity, light-induced entrainment, molecular clockwork, as well as melatonin secretion are preserved in the HIP rat model of T2DM. These results suggest that despite the well-characterized ability of glucose to modulate circadian clock gene expression acutely in vitro, SCN clock function and key behavioral and physiological outputs appear to be preserved under chronic diabetic conditions characteristic of nonobese T2DM.

scholarly journals Phase-dependent resetting of the adrenal clock by ACTH in vitro

2014 ◽  
Vol 306 (6) ◽  
pp. R387-R393 ◽  
Author(s):  
J. Marina Yoder ◽  
Megan Brandeland ◽  
William C. Engeland
Keyword(s):  
Circadian Rhythms ◽  
Molecular Clock ◽  
Clock Gene ◽  
External Environment ◽  
Phase Delay ◽  
Melanocyte Stimulating Hormone ◽  
Circadian Time ◽  
Acth Receptor ◽  
Acth Fragments

The adrenal cortex has a molecular clock that generates circadian rhythms in glucocorticoids, yet how the clock is synchronized to the external environment is unknown. Using mPER2::Luciferase (mPER2Luc) knockin mice, in which luciferase is rhythmically expressed under the control of the mouse Per2 clock gene, we hypothesized that ACTH transmits entrainment signals to the adrenal. Adrenal explants were administered ACTH at different phases of the mPER2Luc rhythm. Treatment with ACTH 1–39 produced a phase delay that was phase-dependent, with a maximum at circadian time (CT)18; ACTH did not alter the period or amplitude of the rhythm. Forskolin produced a parallel response, suggesting that the phase delay was cAMP-mediated. The response to ACTH was concentration-dependent and peptide-specific. Pulse administration (60 min) of ACTH 1–39 also produced phase delays restricted to late CTs. In contrast to ACTH 1–39, other ACTH fragments, including α-melanocyte-stimulating hormone, which do not activate the melanocortin 2 (MC2/ACTH) receptor, had no effect. The finding that ACTH in vitro phase delays the adrenal mPER2luc rhythm in a monophasic fashion argues for ACTH as a key resetter, but not the sole entrainer, of the adrenal clock.

scholarly journals Lateralization of the central circadian pacemaker output: a test of neural control of peripheral oscillator phase

2010 ◽  
Vol 299 (3) ◽  
pp. R751-R761 ◽  
Author(s):  
Carrie E. Mahoney ◽  
Daniel Brewer ◽  
Mary K. Costello ◽  
Judy McKinley Brewer ◽  
Eric L. Bittman
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Adrenal Medulla ◽  
Neural Control ◽  
Clock Gene ◽  
Neural Pathways ◽  
Peripheral Organs ◽  
Peripheral Oscillators ◽  
Clock Gene Expression ◽  
Oscillator Phase

To evaluate the contribution of neural pathways to the determination of the circadian oscillator phase in peripheral organs, we assessed lateralization of clock gene expression in Syrian hamsters induced to split rhythms of locomotor activity by exposure to constant light. We measured the ratio of haPer1, haPer2, and haBmal1 mRNA on the high vs. low (H/L) side at 3-h intervals prior to the predicted activity onset (pAO). We also calculated expression on the sides ipsilateral vs. contralateral (I/C) to the side of the suprachiasmatic nucleus (SCN) expressing higher haPer1. The extent of asymmetry in split hamsters varied between specific genes, phases, and organs. Although the magnitude of asymmetry in peripheral organs was never as great as that in the SCN, we observed significantly greater lateralization of clock gene expression in the adrenal medulla and cortex, lung, and skeletal muscle, but not in liver or kidney, of split hamsters than of unsplit controls. We observed fivefold lateralization of expression of the clock-controlled gene, albumin site D-element binding protein ( Dbp), in skeletal muscle (H/L: 10.7 ± 3.7 at 3 h vs. 2.2 ± 0.3 at 0 h pAO; P = 0.03). Furthermore, tyrosine hydroxylase expression was asymmetrical in the adrenal medulla of split (H/L: 1.9 ± 0.5 at 0 h) vs. unsplit hamsters (1.2 ± 0.04; P < 0.05). Consistent with a model of neurally controlled gene expression, we found significant correlations between the phase angle between morning and evening components (ψme) and the level of asymmetry (H/L or I/C). Our results indicate that neural pathways contribute to, but cannot completely account for, SCN regulation of the phase of peripheral oscillators.

scholarly journals Physiology of Circadian Entrainment

2010 ◽  
Vol 90 (3) ◽  
pp. 1063-1102 ◽  
Author(s):  
Diego A. Golombek ◽  
Ruth E. Rosenstein
Keyword(s):  
Circadian Rhythms ◽  
Clock Gene ◽  
Retinal Diseases ◽  
Suprachiasmatic Nuclei ◽  
Circadian Variations ◽  
Dark Cycle ◽  
Clock Gene Expression ◽  
Biological Oscillators ◽  
Pituitary Adenylate Cyclase ◽  
Neurotransmitter Glutamate

Mammalian circadian rhythms are controlled by endogenous biological oscillators, including a master clock located in the hypothalamic suprachiasmatic nuclei (SCN). Since the period of this oscillation is of ∼24 h, to keep synchrony with the environment, circadian rhythms need to be entrained daily by means of Zeitgeber (“time giver”) signals, such as the light-dark cycle. Recent advances in the neurophysiology and molecular biology of circadian rhythmicity allow a better understanding of synchronization. In this review we cover several aspects of the mechanisms for photic entrainment of mammalian circadian rhythms, including retinal sensitivity to light by means of novel photopigments as well as circadian variations in the retina that contribute to the regulation of retinal physiology. Downstream from the retina, we examine retinohypothalamic communication through neurotransmitter (glutamate, aspartate, pituitary adenylate cyclase-activating polypeptide) interaction with SCN receptors and the resulting signal transduction pathways in suprachiasmatic neurons, as well as putative neuron-glia interactions. Finally, we describe and analyze clock gene expression and its importance in entrainment mechanisms, as well as circadian disorders or retinal diseases related to entrainment deficits, including experimental and clinical treatments.

scholarly journals Neuron-specific knockouts indicate the importance of network communication to Drosophila rhythmicity

2019 ◽  
Author(s):  
M Schlichting ◽  
MM Diaz ◽  
J Xin ◽  
M Rosbash
Keyword(s):  
Gene Expression ◽  
Circadian Rhythms ◽  
Intercellular Communication ◽  
Clock Gene ◽  
Feedback Loops ◽  
Neuronal Firing ◽  
Network Communication ◽  
Constant Darkness ◽  
Circadian Period ◽  
Clock Gene Expression

AbstractAnimal circadian rhythms persist in constant darkness and are driven by intracellular transcription-translation feedback loops. Although these cellular oscillators communicate, isolated mammalian cellular clocks continue to tick away in darkness without intercellular communication. To investigate these issues in Drosophila, we assayed behavior as well as molecular rhythms within individual brain clock neurons while blocking communication within the ca. 150 neuron clock network. We also generated CRISPR-mediated neuron-specific circadian clock knockouts. The results point to two key clock neuron groups: loss of the clock within both regions but neither one alone has a strong behavioral phenotype in darkness; communication between these regions also contributes to circadian period determination. Under these dark conditions, the clock within one region persists without network communication. The clock within the famous PDF-expressing s-LNv neurons however was strongly dependent on network communication, likely because clock gene expression within these vulnerable sLNvs depends on neuronal firing or light.

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