Salt-inducible kinase 3 regulates the mammalian circadian clock by destabilizing PER2 protein
- Nagoya University, Japan
- The University of Tokyo, Japan
- Kindai University, Japan
- Ritsumeikan University, Japan
- National Institutes of Biomedical Innovation, Health and Nutrition, Japan
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
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.
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Salt-inducible kinase 3 regulates the mammalian circadian clock by destabilizing PER2 protein
eLife 6:e24779.
https://doi.org/10.7554/eLife.24779
Further reading
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- Neuroscience
The relation between neural activity and behaviorally relevant variables is at the heart of neuroscience research. When strong, this relation is termed a neural representation. There is increasing evidence, however, for partial dissociations between activity in an area and relevant external variables. While many explanations have been proposed, a theoretical framework for the relationship between external and internal variables is lacking. Here, we utilize recurrent neural networks (RNNs) to explore the question of when and how neural dynamics and the network’s output are related from a geometrical point of view. We find that training RNNs can lead to two dynamical regimes: dynamics can either be aligned with the directions that generate output variables, or oblique to them. We show that the choice of readout weight magnitude before training can serve as a control knob between the regimes, similar to recent findings in feedforward networks. These regimes are functionally distinct. Oblique networks are more heterogeneous and suppress noise in their output directions. They are furthermore more robust to perturbations along the output directions. Crucially, the oblique regime is specific to recurrent (but not feedforward) networks, arising from dynamical stability considerations. Finally, we show that tendencies toward the aligned or the oblique regime can be dissociated in neural recordings. Altogether, our results open a new perspective for interpreting neural activity by relating network dynamics and their output.
