Lhx1 controls terminal differentiation and circadian function of the suprachiasmatic nucleus.
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.
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Joseph L
JL
Bedont
Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
Tara A
TA
LeGates
Department of Biology, Washington University, St. Louis, MO 63130, USA.
Emily A
EA
Slat
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Mardi S
MS
Byerly
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Hong
H
Wang
Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Jianfei
J
Hu
Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
Alan C
AC
Rupp
Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Jiang
J
Qian
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.
G William
GW
Wong
Department of Biology, Washington University, St. Louis, MO 63130, USA.
Erik D
ED
Herzog
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
Samer
S
Hattar
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.
Seth
S
Blackshaw
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002940:Circadian Rhythm / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D005838:Genotype; D060850:LIM-Homeodomain Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000378:metabolism; D013493:Suprachiasmatic Nucleus / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D060850:LIM-Homeodomain Proteins; C499523:Lhx1 protein, mouse; D009479:Neuropeptides; D014157:Transcription Factors