1. Neuroscience

Salt-inducible kinase 3 regulates the mammalian circadian clock by destabilizing PER2 protein

  1. Naoto Hayasaka  Is a corresponding author
  2. Arisa Hirano
  3. Yuka Miyoshi
  4. Isao T Tokuda
  5. Hikari Yoshitane
  6. Junichiro Matsuda
  7. Yoshitaka Fukada
  1. Nagoya University, Japan
  2. The University of Tokyo, Japan
  3. Kindai University, Japan
  4. Ritsumeikan University, Japan
  5. National Institutes of Biomedical Innovation, Health and Nutrition, Japan
https://doi.org/10.7554/eLife.24779
Share this article
Cite this article
  1. Naoto Hayasaka
  2. Arisa Hirano
  3. Yuka Miyoshi
  4. Isao T Tokuda
  5. Hikari Yoshitane
  6. Junichiro Matsuda
  7. Yoshitaka Fukada
(2017)
Salt-inducible kinase 3 regulates the mammalian circadian clock by destabilizing PER2 protein
eLife 6:e24779.
https://doi.org/10.7554/eLife.24779
  2. Download BibTeX
  3. Download .RIS

Abstract

Salt-inducible kinase 3 (SIK3) plays a crucial role in various aspects of metabolism. In the course of investigating metabolic defects in Sik3-deficient mice (Sik3-/-), we observed that circadian rhythmicity of the metabolisms was phase-delayed. Sik3-/- mice also exhibited other circadian abnormalities, including lengthening of the period, impaired entrainment to the light-dark cycle, phase variation in locomotor activities, and aberrant physiological rhythms. Ex vivosuprachiasmatic nucleus slices from Sik3-/- mice exhibited destabilized and desynchronized molecular rhythms among individual neurons. In cultured cells, Sik3-knockdown resulted in abnormal bioluminescence rhythms. Expression levels of PER2, a clock protein, were elevated in Sik3-knockdown cells but down-regulated in Sik3-overexpressing cells, which could be attributed to a phosphorylation-dependent decrease in PER2 protein stability. This was further confirmed by PER2 accumulation in the Sik3-/- fibroblasts and liver. Collectively, SIK3 plays key roles in circadian rhythms by facilitating phosphorylation-dependent PER2 destabilization, either directly or indirectly.

Article and author information

Author details

  1. Naoto Hayasaka

    Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
    For correspondence
    naotohayasaka@yahoo.co.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2844-524X

  2. Arisa Hirano

    Department of Biological Sciences, The University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.

  3. Yuka Miyoshi

    Department of Anatomy and Neurobiology, Kindai University, Osaka, Japan
    Competing interests
    The authors declare that no competing interests exist.

  4. Isao T Tokuda

    Department of Mechanical Engineering, Ritsumeikan University, Kusatsu, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6212-0022

  5. Hikari Yoshitane

    Department of Biological Sciences, The University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.

  6. Junichiro Matsuda

    Laboratory of Animal Models for Human Diseases, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
    Competing interests
    The authors declare that no competing interests exist.

  7. Yoshitaka Fukada

    Department of Biological Sciences, The University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.

Funding

Japan Society for the Promotion of Science (Grant-in-Aid for Scientific Research 25293053)

  • Naoto Hayasaka

Japan Science and Technology Agency (PRESTO)

  • Naoto Hayasaka

Japan Society for the Promotion of Science (Grant-in-Aid for Scientific Research 24227001)

  • Yoshitaka Fukada

Japan Society for the Promotion of Science (Grant-in-Aid for Scientific Research 17H06096)

  • Yoshitaka Fukada

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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 Japan Society for Promotion of Sciences. All of the animals were handled according to approved institutional animal care and use committees of Kindai University (KAME- 19-051) and Nagoya University (17239).

Copyright

© 2017, Hayasaka 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

  • 4,460
    views
  • 666
    downloads
  • 34
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  1. Naoto Hayasaka
  2. Arisa Hirano
  3. Yuka Miyoshi
  4. Isao T Tokuda
  5. Hikari Yoshitane
  6. Junichiro Matsuda
  7. Yoshitaka Fukada
(2017)
Salt-inducible kinase 3 regulates the mammalian circadian clock by destabilizing PER2 protein
eLife 6:e24779.
https://doi.org/10.7554/eLife.24779

Share this article

https://doi.org/10.7554/eLife.24779

Categories and tags

Research organism

Further reading

    1. Cancer Biology
    2. Neuroscience

    Tumor-infiltrating nerves functionally alter brain circuits and modulate behavior in a mouse model of head-and-neck cancer

    Jeffrey Barr, Austin Walz ... Paola D Vermeer
    Research Article

    Cancer patients often experience changes in mental health, prompting an exploration into whether nerves infiltrating tumors contribute to these alterations by impacting brain functions. Using a mouse model for head and neck cancer and neuronal tracing, we show that tumor-infiltrating nerves connect to distinct brain areas. The activation of this neuronal circuitry altered behaviors (decreased nest-building, increased latency to eat a cookie, and reduced wheel running). Tumor-infiltrating nociceptor neurons exhibited heightened calcium activity and brain regions receiving these neural projections showed elevated Fos as well as increased calcium responses compared to non-tumor-bearing counterparts. The genetic elimination of nociceptor neurons decreased brain Fos expression and mitigated the behavioral alterations induced by the presence of the tumor. While analgesic treatment restored nesting and cookie test behaviors, it did not fully restore voluntary wheel running indicating that pain is not the exclusive driver of such behavioral shifts. Unraveling the interaction between the tumor, infiltrating nerves, and the brain is pivotal to developing targeted interventions to alleviate the mental health burdens associated with cancer.

    1. Neuroscience

    Sensitivity to vocal emotions emerges in newborns at 37 weeks gestational age

    Xinlin Hou, Peng Zhang ... Dandan Zhang
    Research Article

    Emotional responsiveness in neonates, particularly their ability to discern vocal emotions, plays an evolutionarily adaptive role in human communication and adaptive behaviors. The developmental trajectory of emotional sensitivity in neonates is crucial for understanding the foundations of early social-emotional functioning. However, the precise onset of this sensitivity and its relationship with gestational age (GA) remain subjects of investigation. In a study involving 120 healthy neonates categorized into six groups based on their GA (ranging from 35 and 40 weeks), we explored their emotional responses to vocal stimuli. These stimuli encompassed disyllables with happy and neutral prosodies, alongside acoustically matched nonvocal control sounds. The assessments occurred during natural sleep states using the odd-ball paradigm and event-related potentials. The results reveal a distinct developmental change at 37 weeks GA, marking the point at which neonates exhibit heightened perceptual acuity for emotional vocal expressions. This newfound ability is substantiated by the presence of the mismatch response, akin to an initial form of adult mismatch negativity, elicited in response to positive emotional vocal prosody. Notably, this perceptual shift’s specificity becomes evident when no such discrimination is observed in acoustically matched control sounds. Neonates born before 37 weeks GA do not display this level of discrimination ability. This developmental change has important implications for our understanding of early social-emotional development, highlighting the role of gestational age in shaping early perceptual abilities. Moreover, while these findings introduce the potential for a valuable screening tool for conditions like autism, characterized by atypical social-emotional functions, it is important to note that the current data are not yet robust enough to fully support this application. This study makes a substantial contribution to the broader field of developmental neuroscience and holds promise for future research on early intervention in neurodevelopmental disorders.