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Proc Natl Acad Sci U S A. 2017 Sep 5;114(36):E7479-E7488. doi: 10.1073/pnas.1703170114. Epub 2017 Aug 21.

Involvement of posttranscriptional regulation of Clock in the emergence of circadian clock oscillation during mouse development.

Author information

1
Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
2
Faculty of Biology, Medicine and Health, Wellcome Trust Centre for Cell Matrix Research, University of Manchester, Manchester M13 9PL, United Kingdom.
3
Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; kyagita@koto.kpu-m.ac.jp.

Abstract

Circadian clock oscillation emerges in mouse embryo in the later developmental stages. Although circadian clock development is closely correlated with cellular differentiation, the mechanisms of its emergence during mammalian development are not well understood. Here, we demonstrate an essential role of the posttranscriptional regulation of Clock subsequent to the cellular differentiation for the emergence of circadian clock oscillation in mouse fetal hearts and mouse embryonic stem cells (ESCs). In mouse fetal hearts, no apparent oscillation of cell-autonomous molecular clock was detectable around E10, whereas oscillation was clearly visible in E18 hearts. Temporal RNA-sequencing analysis using mouse fetal hearts reveals many fewer rhythmic genes in E10-12 hearts (63, no core circadian genes) than in E17-19 hearts (483 genes), suggesting the lack of functional circadian transcriptional/translational feedback loops (TTFLs) of core circadian genes in E10 mouse fetal hearts. In both ESCs and E10 embryos, CLOCK protein was absent despite the expression of Clock mRNA, which we showed was due to Dicer/Dgcr8-dependent translational suppression of CLOCK. The CLOCK protein is required for the discernible molecular oscillation in differentiated cells, and the posttranscriptional regulation of Clock plays a role in setting the timing for the emergence of the circadian clock oscillation during mammalian development.

KEYWORDS:

CLOCK; cellular differentiation; circadian clock; ontogeny; posttranscriptional regulation

PMID:
28827343
PMCID:
PMC5594651
DOI:
10.1073/pnas.1703170114
[Indexed for MEDLINE]
Free PMC Article

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