title: An LHX1-Regulated Transcriptional Network Controls Sleep/Wake Coupling and Thermal Resistance of the Central Circadian Clockworks.
abstract: The suprachiasmatic nucleus (SCN) is the central circadian clock in mammals. It is entrained by light but resistant to temperature shifts that entrain peripheral clocks [1-5]. The SCN expresses many functionally important neuropeptides, including vasoactive intestinal peptide (VIP), which drives light entrainment, synchrony, and amplitude of SCN cellular clocks and organizes circadian behavior [5-16]. The transcription factor LHX1 drives SCN Vip expression, and cellular desynchrony in Lhx1-deficient SCN largely results from Vip loss [17, 18]. LHX1 regulates many genes other than Vip, yet activity rhythms in Lhx1-deficient mice are similar to Vip-/-mice under light-dark cycles and only somewhat worse in constant conditions. We suspected that LHX1 targets other than Vip have circadian functions overlooked in previous studies. In this study, we compared circadian sleep and temperature rhythms of Lhx1- and Vip-deficient mice and found loss of acute light control of sleep in Lhx1 but not Vip mutants. We also found loss of circadian resistance to fever in Lhx1 but not Vip mice, which was partially recapitulated by heat application to cultured Lhx1-deficient SCN. Having identified VIP-independent functions of LHX1, we mapped the VIP-independent transcriptional network downstream of LHX1 and a largely separable VIP-dependent transcriptional network. The VIP-independent network does not affect core clock amplitude and synchrony, unlike the VIP-dependent network. These studies identify Lhx1 as the first gene required for temperature resistance of the SCN clockworks and demonstrate that acute light control of sleep is routed through the SCN and its immediate output regions.
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Bedont
authors.affiliation: Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Tara A
authors.initials: TA
authors.lastname: LeGates
authors.affiliation: Department of Ophthalmology, University of Washington, Seattle, WA 98104, USA.
authors.forename: Ethan
authors.initials: E
authors.lastname: Buhr
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Abhijith
authors.initials: A
authors.lastname: Bathini
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Ling
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bell
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Wu
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Wong
authors.affiliation: Department of Ophthalmology, University of Washington, Seattle, WA 98104, USA.
authors.forename: Russell N
authors.initials: RN
authors.lastname: Van Gelder
authors.affiliation: Department of Neuroscience, Université de Montreal, Montreal, QC H3C 3J7, Canada.
authors.forename: Valerie
authors.initials: V
authors.lastname: Mongrain
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA. Electronic address: samer.hattar@gmail.com.
authors.forename: Samer
authors.initials: S
authors.lastname: Hattar
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Center for Human Systems Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address: sblack@jhmi.edu.
authors.forename: Seth
authors.initials: S
authors.lastname: Blackshaw
mesh_terms: D000818:Animals; D057906:Circadian Clocks; D002940:Circadian Rhythm; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D059014:High-Throughput Nucleotide Sequencing; D006358:Hot Temperature; D060850:LIM-Homeodomain Proteins / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017440:Photoperiod; D015398:Signal Transduction; D012890:Sleep; D013493:Suprachiasmatic Nucleus / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D014660:Vasoactive Intestinal Peptide / Q000502:physiology*; D014851:Wakefulness
chemical_list: D060850:LIM-Homeodomain Proteins; C499523:Lhx1 protein, mouse; D014157:Transcription Factors; D014660:Vasoactive Intestinal Peptide
keywords: LHX1; LPS; SCN; VIP; circadian; light; resistance; sleep; temperature; transcriptome