Bioluminescence imaging of individual fibroblasts reveals persistent, independently phased circadian rhythms of clock gene expression
Open accessAbstract
Circadian (ca. 24 hr) oscillations in expression of mammalian "clock genes" are found not only in the suprachiasmatic nucleus (SCN), the central circadian pacemaker, but also in peripheral tissues. Under constant conditions in vitro, however, rhythms of peripheral tissue explants or immortalized cells damp partially or completely. It is unknown whether this reflects an inability of peripheral cells to sustain rhythms, as SCN neurons can, or a loss of synchrony among cells. Using bioluminescence imaging of Rat-1 fibroblasts transfected with a Bmal1::luc plasmid and primary fibroblasts dissociated from mPer2(Luciferase-SV40) knockin mice, we monitored single-cell circadian rhythms of clock gene expression for 1-2 weeks. We found that single fibroblasts can oscillate robustly and independently with undiminished amplitude and diverse circadian periods. Cells were partially synchronized by medium changes at the start of an experiment, but due to different intrinsic periods, their phases became randomly distributed after several days. Closely spaced cells in the same culture did not have similar phases, implying a lack of functional coupling among cells. Thus, like SCN neurons, single fibroblasts can function as independent circadian oscillators; however, lack of oscillator coupling in dissociated cell cultures leads to a loss of synchrony among individual cells and damping of the ensemble rhythm at the population level.
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Intercellular coupling of circadian oscillators can compensate for genetic deficiencies in individual clock components.
“Because intercellular coupling of circadian oscillators can compensate for genetic deficiencies in individual clock components, further understanding of the regulation of coupling could provide novel insight into the mechanisms of increasing”
From Biological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges (2009) · cites this paper as Welsh et al., 2004
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- Authors
- Welsh, D. K., Yoo, S.-H., Liu, A. C., Takahashi, J. S., & Kay, S. A.
- Affiliations
- Scripps Research Institute (US)
- Northwestern University (US)
- Corresponding author
- Welsh, David K.
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2004-12
- Volume
- 14
- Issue
- 24
- Pages
- 2289-2295
- ISSN
- 0960-9822 (ISSN-L)
- PMC
- PMC3777438
- OpenAlex
- W2143506081
- Cited by
- 726
- References
- 34
- Citations by year
- 2026: 9 · 2025: 18 · 2024: 25 · 2023: 19 · 2022: 25 · 2021: 32 · 2020: 51 · 2019: 30 · 2018: 30 · 2017: 40 · 2016: 36 · 2015: 35 · 2014: 38 · 2013: 36 · 2012: 42
- FWCI
- 13.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 3150 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Mental Health (K08MH067657, MH-51573, R01MH051573)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Physical Sciences › Computer Science › Computer Networks and Communications › Nonlinear Dynamics and Pattern Formation
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and Work-Related Fatigue
- Keywords
- circadian rhythm, clock genes, fibroblasts, Bmal1, Per2, oscillator coupling, phase synchronization, suprachiasmatic nucleus, circadian period
- MeSH terms
- Animals, Cells, Cultured, Circadian Rhythm, Fibroblasts, Gene Expression Regulation, Image Processing, Computer-Assisted, Luciferases, Mice, Mutant Strains, Oscillometry, Trans-Activators, DNA Primers, Mice, CLOCK Proteins
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