1. Genetics and Genomics
  2. Neuroscience
Download icon

Lhx1 maintains synchrony among circadian oscillator neurons of the SCN

  1. Megumi Hatori
  2. Shubhroz Gill
  3. Ludovic S Mure
  4. Martyn Goulding
  5. Dennis DM O'Leary
  6. Satchidananda Panda  Is a corresponding author
  1. Keio University, Japan
  2. Salk Institute for Biological Studies, United States
Research Article
  • Cited 44
  • Views 5,274
  • Annotations
Cite this article as: eLife 2014;3:e03357 doi: 10.7554/eLife.03357

Abstract

The robustness and limited plasticity of the master circadian clock in the suprachiasmatic nucleus (SCN) is attributed to strong intercellular communication among its constituent neurons. However, factors that specify this characteristic feature of the SCN are unknown. Here we identified Lhx1 as a regulator of SCN coupling. A phase-shifting light pulse causes acute reduction in Lhx1 expression and of its target genes that participate in SCN coupling. Mice lacking Lhx1 in the SCN have intact circadian oscillators, but reduced levels of coupling factors. Consequently, the mice rapidly phase shift under a jet lag paradigm and their behavior rhythms gradually deteriorate under constant condition. Ex vivo recordings of the SCN from these mice showed rapid desynchronization of unit oscillators. Therefore, by regulating expression of genes mediating intercellular communication, Lhx1 imparts synchrony among SCN neurons and ensures consolidated rhythms of activity and rest that is resistant to photic noise.

Article and author information

Author details

  1. Megumi Hatori

    Keio University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  2. Shubhroz Gill

    Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ludovic S Mure

    Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Martyn Goulding

    Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Dennis DM O'Leary

    Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Satchidananda Panda

    Salk Institute for Biological Studies, La Jolla, United States
    For correspondence
    panda@salk.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#12-00026) of the Salk Institute for Biological Studies. The protocol was approved by the IACUC committee of the Salk Institute. All surgery was performed under IACUC approved anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Louis Ptáček, University of California, San Francisco, United States

Publication history

  1. Received: May 13, 2014
  2. Accepted: July 10, 2014
  3. Accepted Manuscript published: July 17, 2014 (version 1)
  4. Version of Record published: August 20, 2014 (version 2)

Copyright

© 2014, Hatori et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 5,274
    Page views
  • 459
    Downloads
  • 44
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

  1. Further reading

Further reading

    1. Genetics and Genomics
    Kathleen Greenham et al.
    Research Article

    An important challenge of crop improvement strategies is assigning function to paralogs in polyploid crops. Here, we describe the circadian transcriptome in the polyploid crop Brassica rapa. Strikingly, almost three quarters of expressed genes exhibited circadian rhythmicity. Genetic redundancy resulting from whole genome duplication is thought to facilitate evolutionary change through sub- and neo-functionalization among paralogous gene pairs. We observed genome-wide expansion of circadian expression phase among retained paralogous pairs. Using gene regulatory network models, we compared transcription factor targets between B. rapa and Arabidopsis circadian networks to reveal evidence for divergence between B. rapa paralogs that may be driven in part by variation in conserved non-coding sequences (CNS). Additionally, differential drought response among retained paralogous pairs suggests further functional diversification. These findings support the rapid expansion and divergence of the transcriptional network in a polyploid crop and offer a new approach for assessing paralog activity at the transcript level.

    1. Genetics and Genomics
    2. Neuroscience
    Marina Kovalenko et al.
    Research Article

    Somatic expansion of the Huntington's disease (HD) CAG repeat drives the rate of a pathogenic process ultimately resulting in neuronal cell death. Although mechanisms of toxicity are poorly delineated, transcriptional dysregulation is a likely contributor. To identify modifiers that act at the level of CAG expansion and/or downstream pathogenic processes, we tested the impact of genetic knockout, in HttQ111 mice, of Hdac2 or Hdac3 in medium-spiny striatal neurons that exhibit extensive CAG expansion and exquisite disease vulnerability. Both knockouts moderately attenuated CAG expansion, with Hdac2 knockout decreasing nuclear huntingtin pathology. Hdac2 knockout resulted in a substantial transcriptional response that included modification of transcriptional dysregulation elicited by the HttQ111 allele, likely via mechanisms unrelated to instability suppression. Our results identify novel modifiers of different aspects of HD pathogenesis in MSNs and highlight a complex relationship between the expanded Htt allele and Hdac2 with implications for targeting transcriptional dysregulation in HD.