Intercellular coupling confers robustness against mutations in the SCN circadian clock network.
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.
Liu
Andrew C
AC
Department of Biochemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
Welsh
David K
DK
Ko
Caroline H
CH
Tran
Hien G
HG
Zhang
Eric E
EE
Priest
Aaron A
AA
Buhr
Ethan D
ED
Singer
Oded
O
Meeker
Kirsten
K
Verma
Inder M
IM
Doyle
Francis J
FJ
Takahashi
Joseph S
JS
Kay
Steve A
SA
D000818:Animals; D001683:Biological Clocks / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000502:physiology*; D056931:Cryptochromes; D005347:Fibroblasts; D005420:Flavoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009043:Motor Activity; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D056950:Period Circadian Proteins; D013493:Suprachiasmatic Nucleus / Q000166:cytology / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D018797:Cell Cycle Proteins; C538964:Cry1 protein, mouse; C538967:Cry2 protein, mouse; D056931:Cryptochromes; D005420:Flavoproteins; D009687:Nuclear Proteins; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; C512645:Per3 protein, mouse; D056950:Period Circadian Proteins; D014157:Transcription Factors