Lhx1 controls terminal differentiation and circadian function of the suprachiasmatic nucleus

Joseph L Bedont; Tara A LeGates; Emily A Slat; Mardi S Byerly; Hong Wang; Jianfei Hu; Alan C Rupp; Jiang Qian; G William Wong; Erik D Herzog; Samer Hattar; Seth Blackshaw

doi:10.1016/j.celrep.2014.03.060

Lhx1 controls terminal differentiation and circadian function of the suprachiasmatic nucleus

Cell Rep. 2014 May 8;7(3):609-22. doi: 10.1016/j.celrep.2014.03.060. Epub 2014 Apr 24.

Authors

Joseph L Bedont¹, Tara A LeGates², Emily A Slat³, Mardi S Byerly⁴, Hong Wang¹, Jianfei Hu⁵, Alan C Rupp², Jiang Qian⁵, G William Wong⁶, Erik D Herzog³, Samer Hattar⁷, Seth Blackshaw⁸

Affiliations

¹ 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 Biology, Washington University, St. Louis, MO 63130, USA.
⁴ Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁵ Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁶ Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁷ Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
⁸ Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Center for High-Throughput 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.

Abstract

Vertebrate circadian rhythms are organized by the hypothalamic suprachiasmatic nucleus (SCN). Despite its physiological importance, SCN development is poorly understood. Here, we show that Lim homeodomain transcription factor 1 (Lhx1) is essential for terminal differentiation and function of the SCN. Deletion of Lhx1 in the developing SCN results in loss of SCN-enriched neuropeptides involved in synchronization and coupling to downstream oscillators, among other aspects of circadian function. Intact, albeit damped, clock gene expression rhythms persist in Lhx1-deficient SCN; however, circadian activity rhythms are highly disorganized and susceptible to surprising changes in period, phase, and consolidation following neuropeptide infusion. Our results identify a factor required for SCN terminal differentiation. In addition, our in vivo study of combinatorial SCN neuropeptide disruption uncovered synergies among SCN-enriched neuropeptides in regulating normal circadian function. These animals provide a platform for studying the central oscillator's role in physiology and cognition.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Cell Differentiation*
Circadian Rhythm / physiology*
Female
Gene Expression
Genotype
LIM-Homeodomain Proteins / deficiency
LIM-Homeodomain Proteins / genetics
LIM-Homeodomain Proteins / metabolism*
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neuropeptides / metabolism
Suprachiasmatic Nucleus / cytology*
Suprachiasmatic Nucleus / metabolism
Transcription Factors / deficiency
Transcription Factors / genetics
Transcription Factors / metabolism*

Substances

LIM-Homeodomain Proteins
Lhx1 protein, mouse
Neuropeptides
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding