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Time after time: circadian clock regulation of intestinal stem cells

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Abstract

Daily fluctuations in animal physiology, known as circadian rhythms, are orchestrated by a conserved molecular timekeeper, known as the circadian clock. The circadian clock forms a transcription–translation feedback loop that has emerged as a central biological regulator of many 24-h processes. Early studies of the intestine discovered that many digestive functions have a daily rhythm and that intestinal cell production was similarly time-dependent. As genetic methods in model organisms have become available, it has become apparent that the circadian clock regulates many basic cellular functions, including growth, proliferation, and differentiation, as well as cell signalling and stem cell self-renewal. Recent connections between circadian rhythms and immune system function, and between circadian rhythms and microbiome dynamics, have also been revealed in the intestine. These processes are highly relevant in understanding intestinal stem cell biology. Here we describe the circadian clock regulation of intestinal stem cells primarily in two model organisms: Drosophila melanogaster and mice. Like all cells in the body, intestinal stem cells are subject to circadian timing, and both cell-intrinsic and cell-extrinsic circadian processes contribute to their function.

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Abbreviations

Apc:

Adenomatous polyposis complex

Ascl2:

Achaete scute-like homolog 2

Bmal1:

Brain and muscle Aryl hydrocarbon receptor nuclear translocator like

Bmi1:

B-cell-specific moloney murine leukemia virus integration site 1

Bmp:

Bone morphogenic protein

CBC:

Crypt base columnar cell

ChIP:

Chromatin immunoprecipitation

Chk:

Checkpoint kinase

Ck1:

Casein kinase 1

Clk:

Clock

Clock:

Circadian locomotor output cycles kaput

Cry:

Cryptochrome

Cxcl12:

C-X-C chemokine ligand 12

Cxcr4:

C-X-C chemokine receptor type 4

Cyc:

Cycle

Gsk3:

Glycogen synthase kinase 3

Hopx:

Homeoboxdomain-only protein

IBD:

Inflammatory bowel disease

IL:

Interleukin

ISC:

Intestinal stem cell

Jak/Stat:

Janus kinase/signal transducers and activators of transcription

Klf9:

Kruppel-like factor 9

Lgr5:

Leucine-rich repeat-containing G-protein coupled receptor 5

Lrig1:

Leucine-rich repeats and immunoglobin-like domains-protein 1

Lrp:

Low density lipoprotein receptor

Mapk:

Mitogen-activated protein kinase

mTOR:

Mammalian target of rapamycin

Olfm4:

Olfactomedin 4

Per:

Period

Ror:

Retinoic acid receptor-related orphan receptors

S6K:

S6 kinase

Sirt1:

Sirtuin-1

Tert1:

Telomerase reverse transcriptase

Tim:

Timeless

Tnf:

Tumour necrosis factor

Upd:

Unpaired

Vri:

Vrille

Pdp1:

PAR domain protein-1

Wee1:

Wee1 G2 checkpoint kinase

Xpa:

Xeroderma pigmentosum group A

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Acknowledgements

We thank all members of the Karpowicz lab for their help. This work was supported by grants from the Natural Sciences and Engineering Research Council of Canada (#2015-03656), the Canadian Institutes of Health Research (#388014), the Ontario Institute for Regenerative Medicine, and Crohn’s and Colitis Canada.

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  1. Department of Biological Sciences, University of Windsor, 401 Sunset Avenue, Windsor, ON, N9B 3P4, Canada

    Kathyani Parasram & Phillip Karpowicz

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  1. Kathyani Parasram
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  2. Phillip Karpowicz
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Correspondence to Phillip Karpowicz.

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Parasram, K., Karpowicz, P. Time after time: circadian clock regulation of intestinal stem cells. Cell. Mol. Life Sci. 77, 1267–1288 (2020). https://doi.org/10.1007/s00018-019-03323-x

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  • DOI: https://doi.org/10.1007/s00018-019-03323-x

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