title: Intercellular Coupling of the Cell Cycle and Circadian Clock in Adult Stem Cell Culture.
abstract: Circadian clock-gated cell division cycles are observed from cyanobacteria to mammals via intracellular molecular connections between these two oscillators. Here we demonstrate WNT-mediated intercellular coupling between the cell cycle and circadian clock in 3D murine intestinal organoids (enteroids). The circadian clock gates a population of cells with heterogeneous cell-cycle times that emerge as 12-hr synchronized cell division cycles. Remarkably, we observe reduced-amplitude oscillations of circadian rhythms in intestinal stem cells and progenitor cells, indicating an intercellular signal arising from differentiated cells governing circadian clock-dependent synchronized cell division cycles. Stochastic simulations and experimental validations reveal Paneth cell-secreted WNT as the key intercellular coupling component linking the circadian clock and cell cycle in enteroids.
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH 45267-0576, USA.
authors.forename: Toru
authors.initials: T
authors.lastname: Matsu-Ura
authors.affiliation: Department of Mathematical Sciences, University of Cincinnati, Cincinnati, OH 45221-0025, USA.
authors.forename: Andrey
authors.initials: A
authors.lastname: Dovzhenok
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH 45267-0576, USA.
authors.forename: Eitaro
authors.initials: E
authors.lastname: Aihara
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229-3039, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Rood
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH 45267-0576, USA.
authors.forename: Hung
authors.initials: H
authors.lastname: Le
authors.affiliation: Division of Biostatistics and Bioinformatics, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267-0056, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH 45267-0576, USA.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Rosselot
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH 45267-0576, USA.
authors.forename: Tongli
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Program in Neuroscience, Department of Biomedical Sciences, College of Medicine, Florida State University, 1115 West Call Street, Tallahassee, FL 32306, USA.
authors.forename: Choogon
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Neuroscience, College of Medicine, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Obrietan
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH 45267-0576, USA.
authors.forename: Marshall H
authors.initials: MH
authors.lastname: Montrose
authors.affiliation: Department of Mathematical Sciences, University of Cincinnati, Cincinnati, OH 45221-0025, USA.
authors.forename: Sookkyung
authors.initials: S
authors.lastname: Lim
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229-3039, USA. Electronic address: sean.moore@virginia.edu.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Moore
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH 45267-0576, USA; Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229-3039, USA. Electronic address: christian.hong@uc.edu.
authors.forename: Christian I
authors.initials: CI
authors.lastname: Hong
mesh_terms: D053687:Adult Stem Cells / Q000502:physiology; D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D057906:Circadian Clocks / Q000502:physiology*; D002940:Circadian Rhythm; D007413:Intestinal Mucosa / Q000502:physiology*; D007583:Jejunum / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009940:Organoids; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D046509:Tissue Culture Techniques; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D011505:Protein-Tyrosine Kinases; C499348:Wee1 protein, mouse
keywords: Paneth cell; WNT signaling; cell cycle; circadian rhythm; coupled oscillators; intercellular coupling; intestinal crypt; intestinal stem cell; progenitor cell