An LHX1-Regulated Transcriptional Network Controls Sleep/Wake Coupling and Thermal Resistance of the Central Circadian Clockworks

Joseph L Bedont; Tara A LeGates; Ethan Buhr; Abhijith Bathini; Jonathan P Ling; Benjamin Bell; Mark N Wu; Philip C Wong; Russell N Van Gelder; Valerie Mongrain; Samer Hattar; Seth Blackshaw

doi:10.1016/j.cub.2016.11.008

An LHX1-Regulated Transcriptional Network Controls Sleep/Wake Coupling and Thermal Resistance of the Central Circadian Clockworks

Curr Biol. 2017 Jan 9;27(1):128-136. doi: 10.1016/j.cub.2016.11.008. Epub 2016 Dec 22.

Authors

Affiliations

¹ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
² Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
³ Department of Ophthalmology, University of Washington, Seattle, WA 98104, USA.
⁴ 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.
⁵ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁶ 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.
⁷ Department of Neuroscience, Université de Montreal, Montreal, QC H3C 3J7, Canada.
⁸ 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: [email protected].
⁹ 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: [email protected].

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.

Keywords: LHX1; LPS; SCN; VIP; circadian; light; resistance; sleep; temperature; transcriptome.

MeSH terms

Animals
Circadian Clocks*
Circadian Rhythm
Gene Expression Regulation
Gene Regulatory Networks*
High-Throughput Nucleotide Sequencing
Hot Temperature
LIM-Homeodomain Proteins / physiology*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Photoperiod
Signal Transduction
Sleep*
Suprachiasmatic Nucleus / cytology
Suprachiasmatic Nucleus / metabolism
Transcription Factors / physiology*
Vasoactive Intestinal Peptide / physiology*
Wakefulness*

Substances

LIM-Homeodomain Proteins
Lhx1 protein, mouse
Transcription Factors
Vasoactive Intestinal Peptide

Abstract

MeSH terms

Substances

Grants and funding