Circadian clock-mediated control of stem cell division and differentiation: beyond night and day

Brown, Steven A.

doi:10.1242/dev.104851

Cited by 94 publications

(87 citation statements)

References 86 publications

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“…Our current results are consistent with previous work and extend these observations by demonstrating that adult beta cell-specific deletion of Bmal1 leads to loss of GSIS (both in vivo and in vitro) and impaired beta cell functional and morphological adaptation to HFD. The use of adult Bmal1 deletion in our study is important given the role of circadian clocks in embryonic development and maturation [10]. …”

Section: Discussionmentioning

confidence: 99%

Bmal1 is required for beta cell compensatory expansion, survival and metabolic adaptation to diet-induced obesity in mice

2016

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Aims/hypothesis Obesity and consequent insulin resistance are known risk factors for type 2 diabetes. A compensatory increase in beta cell function and mass in response to insulin resistance permits maintenance of normal glucose homeostasis, whereas failure to do so results in beta cell failure and type 2 diabetes. Recent evidence suggests that the circadian system is essential for proper metabolic control and regulation of beta cell function. We set out to address the hypothesis that the beta cell circadian clock is essential for the appropriate functional and morphological beta cell response to insulin resistance. Methods We employed conditional deletion of the Bmal1 (also known as Arntl) gene (encoding a key circadian clock transcription factor) in beta cells using the tamoxifen-inducible CreERT recombination system. Upon adulthood, Bmal1 deletion in beta cells was achieved and mice were exposed to either chow or high fat diet (HFD). Changes in diurnal glycaemia, glucose tolerance and insulin secretion were longitudinally monitored in vivo and islet morphology and turnover assessed by immunofluorescence. Isolated islet experiments in vitro were performed to delineate changes in beta cell function and transcriptional regulation of cell proliferation. Results Adult Bmal1 deletion in beta cells resulted in failed metabolic adaptation to HFD characterised by fasting and diurnal hyperglycaemia, glucose intolerance and loss of glucose-stimulated insulin secretion. Importantly, HFD-induced beta cell expansion was absent following beta cell Bmal1 deletion indicating impaired beta cell proliferative and regenerative potential, which was confirmed by assessment of transcriptional profiles in isolated islets. Conclusion/interpretation Results of the study suggest that the beta cell circadian clock is a novel regulator of compensatory beta cell expansion and function in response to increased insulin demand associated with diet-induced obesity.

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Section: Discussionmentioning

confidence: 99%

Bmal1 is required for beta cell compensatory expansion, survival and metabolic adaptation to diet-induced obesity in mice

2016

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“…A functional clock is present in adult stem cells, in which circadian oscillations have been shown to drive proliferation and differentiation, thereby facilitating tissue homeostasis and regeneration 89. Targeting the clock in adult stem cells in vivo by the use of drugs might enhance regeneration after damage.…”

Section: Future Perspectivesmentioning

confidence: 99%

Circadian clocks: from stem cells to tissue homeostasis and regeneration

2017

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The circadian clock is an evolutionarily conserved timekeeper that adapts body physiology to diurnal cycles of around 24 h by influencing a wide variety of processes such as sleep‐to‐wake transitions, feeding and fasting patterns, body temperature, and hormone regulation. The molecular clock machinery comprises a pathway that is driven by rhythmic docking of the transcription factors BMAL1 and CLOCK on clock‐controlled output genes, which results in tissue‐specific oscillatory gene expression programs. Genetic as well as environmental perturbation of the circadian clock has been implicated in various diseases ranging from sleep to metabolic disorders and cancer development. Here, we review the origination of circadian rhythms in stem cells and their function in differentiated cells and organs. We describe how clocks influence stem cell maintenance and organ physiology, as well as how rhythmicity affects lineage commitment, tissue regeneration, and aging.

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“…Cell proliferation and apoptosis are regulated and timed by clock genes and several clock-controlled genes. A zeitgeber time (ZT)-dependent regulation of the cell cycle and synchronization of its phases by the circadian clockwork was shown in the liver and other tissues [[27,28,29], reviewed in [30,31]]. For example, the entry of mitosis is restricted to a specific time of day [28].…”

Section: Introductionmentioning

confidence: 99%

Impact of Melatonin on Zeitgeber Time-Dependent Changes in Cell Proliferation and Apoptosis in the Adult Murine Hypothalamic-Hypophyseal System

et al. 2015

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Background/Aims: Cell proliferation and apoptosis are known to adjust neuroendocrine circuits to the photoperiod. The latter is communicated by melatonin, the hormone secreted by the pineal organ. The present study investigated zeitgeber time (ZT)-dependent changes in cell proliferation and apoptosis in the adult murine neuroendocrine system and their regulation by melatonin. Methods: Adult melatonin-proficient (C3H/HeN) and melatonin-deficient (C57Bl/6J) mice, as well as melatonin-proficient (C3H/HeN) mice with targeted deletion of both melatonin receptor types (MT1 and MT2) were adapted to a 12-hour light, 12-hour dark photoperiod and were sacrificed at ZT00, ZT06, ZT12, and ZT18. Immunohistochemistry for Ki67 and activated caspase-3 served to identify and quantify proliferating and apoptotic cells in the median eminence (ME), hypophyseal pars tuberalis, and pars distalis (PD). Results: ZT-dependent changes in cell proliferation and apoptosis were found exclusively in melatonin-proficient mice with functional MTs. Cell proliferation in the ME and PD showed ZT-dependent changes indicated by an increase at ZT12 (ME) and a decrease at ZT06 (PD). Apoptosis showed ZT-dependent changes in all regions analyzed, indicated by an increase at ZT06. Proliferating and apoptotic cells were found in nearly all cell types residing in the regions analyzed. Conclusions: Our results indicate that ZT-dependent changes in cell proliferation are counterbalanced by ZT-dependent changes in apoptosis exclusively in melatonin-proficient mice with functional MTs. Melatonin signaling appears to be crucial in both the generation and timing of proliferation and apoptosis that serve the high rate of physiological cell turnover in the adult neuroendocrine system.

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Circadian clock-mediated control of stem cell division and differentiation: beyond night and day

Cited by 94 publications

References 86 publications

Bmal1 is required for beta cell compensatory expansion, survival and metabolic adaptation to diet-induced obesity in mice

Bmal1 is required for beta cell compensatory expansion, survival and metabolic adaptation to diet-induced obesity in mice

Circadian clocks: from stem cells to tissue homeostasis and regeneration

Impact of Melatonin on Zeitgeber Time-Dependent Changes in Cell Proliferation and Apoptosis in the Adult Murine Hypothalamic-Hypophyseal System

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