title: The Zfhx3-Mediated Axis Regulates Sleep and Interval Timing in Mice.
abstract: An AT motif-dependent axis, modulated by the transcription factor Zfhx3, influences the circadian clock in mice. In particular, gain of function of Zfhx3 significantly shortens circadian rhythms and alters the transcriptional activity of an important class of neuropeptides that controls intercellular signaling in the suprachiasmatic nucleus (SCN) of the hypothalamus. The ZFHX3/AT axis revealed an important, largely cell-nonautonomous control of the circadian clock. Here, by studying the recently identified circadian mouse mutant Zfhx3(Sci/+), we identify significant effects on sleep homeostasis, a phenomenon that is outside the canonical circadian clock system and that is modulated by the activity of those neuropeptides at a circuit level. We show that the Zfhx3(Sci/+) mutation accelerates the circadian clock at both the hourly scale (i.e., advancing circadian rhythms) and the seconds-to-minutes scale (i.e., anticipating behavioral responses) in mice. The in vivo results are accompanied by a significant presence of sleep targets among protein-protein interactions of the Zfhx3(Sci/+)-dependent network.
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genova, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Balzani
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genova, Italy.
authors.forename: Glenda
authors.initials: G
authors.lastname: Lassi
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genova, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Maggi
authors.affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Sethi
authors.affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parsons
authors.affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Michelle
authors.initials: M
authors.lastname: Simon
authors.affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Nolan
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genova, Italy. Electronic address: valter.tucci@iit.it.
authors.forename: Valter
authors.initials: V
authors.lastname: Tucci
mesh_terms: D000818:Animals; D057906:Circadian Clocks / Q000502:physiology*; D002940:Circadian Rhythm / Q000502:physiology*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000378:metabolism; D060066:Protein Interaction Maps / Q000502:physiology; D012890:Sleep / Q000502:physiology*; D013493:Suprachiasmatic Nucleus / Q000378:metabolism / Q000502:physiology
chemical_list: D018398:Homeodomain Proteins; D009479:Neuropeptides; C489511:Zfhx3 protein, mouse