Intercellular coupling confers robustness against mutations in the SCN circadian clock network.

By A. C. Liu, David K. Welsh, C. H. Ko, Hien G. Tran, E. E. Zhang, Aaron A. Priest, Ethan D. Buhr, O. Singer, Kirsten Meeker, Inder M. Verma and 3 more. Cell, 2007

732 citations recorded by the source corpus.

Molecular mechanisms of the mammalian circadian clock have been studied primarily by genetic perturbation and behavioral analysis. Here, we used bioluminescence imaging to monitor Per2 gene expression in tissues and cells from clock mutant mice. We discovered that Per1 and Cry1 are required for sustained rhythms in peripheral tissues and cells, and in neurons dissociated from the suprachiasmatic nuclei (SCN). Per2 is also required for sustained rhythms, whereas Cry2 and Per3 deficiencies cause only period length defects. However, oscillator network interactions in the SCN can compensate for Per1 or Cry1 deficiency, preserving sustained rhythmicity in mutant SCN slices and behavior. Thus, behavior does not necessarily reflect cell-autonomous clock phenotypes. Our studies reveal previously unappreciated requirements for Per1, Per2, and Cry1 in sustaining cellular circadian rhythmicity and demonstrate that SCN intercellular coupling is essential not only to synchronize component cellular oscillators but also for robustness against genetic perturbations.

Subfields: Cellular and Molecular Neuroscience, Endocrine and Autonomic Systems, Plant Science

View Paper: https://www.semanticscholar.org/paper/d0c632a2989927639c3f494c264a40f1e095bc6e

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. J. Takahashi
2. U. Albrecht
3. C. Green
4. U. Schibler
5. T. Scammell
6. E. Arrigoni
7. J. Lipton

In Endocrine and Autonomic Systems

1. J. Takahashi
2. U. Albrecht
3. C. H. Ko
4. C. Green
5. Ethan D. Buhr
6. J. Mohawk
7. Steve A. Kay
8. David K. Welsh

In Plant Science

1. J. Takahashi
2. U. Albrecht
3. C. H. Ko
4. Ethan D. Buhr
5. C. Green
6. U. Schibler
7. C. Dibner
8. Steve A. Kay

Citations in the corpus

• Suprachiasmatic Nucleus: Cell Autonomy and Network Properties (2010, background): “This is consistent with several studies showing that dispersed mutant cells exhibit periods similar to the behavioral period of corresponding mutant animals in vivo (17, 97, 99, 186).”
• Molecular components of the mammalian circadian clock. (2006, background): “The SCN remains robustly rhythmic in the case of a loss of any single member of the negative limb of the transcriptional feedback cycle (Liu et al. 2007).”
• The mammalian circadian timing system: organization and coordination of central and peripheral clocks. (2010, background): “The single-cell analysis of fibroblasts from Per1 knockout mice performed by us and others (224) revealed that the low-amplitude oscillations exhibited by these cells at the population level are the result of a small fraction of robustly cycling cells and a large fraction of arrhythmic cells.”
• Molecular Architecture of the Mammalian Circadian Clock (2013, background): “Of the two mammalian cryptochromes, only CRY1 can sustain circadian cycling in the absence of compensation from SCN network properties [9, 15], and it requires a significant delay in expression relative to CRY2 that is encoded by multiple clock-regulated promoter elements [54, 55].”
• CENTRAL AND PERIPHERAL CIRCADIAN CLOCKS IN MAMMALS (2012, background): “To address this question, Liu et al. (2007a) examined whether canonical clock mutations previously assessed in vivo affected the SCN and peripheral oscillators in a similar manner.”
• Molecular components of the Mammalian circadian clock. (2013, background): “The SCN remains robustly rhythmic in the case of a loss of any single member of the negative limb of the transcriptional feedback cycle (Liu et al. 2007).”