Development of the circadian oscillator during differentiation of mouse embryonic stem cells in vitro

Feb 6, 2010Proceedings of the National Academy of Sciences of the United States of America

How the internal body clock develops as mouse stem cells grow in the lab

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Abstract

Circadian bioluminescence rhythm is not detected in mouse embryonic stem (ES) cells.

Mouse embryonic stem cells likely lack the regulatory mechanisms for clock gene expression necessary for circadian rhythms.
Circadian clock oscillation can be induced during the differentiation of mouse ES cells without maternal factors.
Reprogramming differentiated cells by expressing specific genes results in the loss of circadian oscillation.
An intrinsic program appears to control circadian oscillator formation during the differentiation of ES cells in vitro.

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The molecular oscillations underlying the generation of circadian rhythmicity in mammals develop gradually during ontogenesis. However, the developmental process of mammalian cellular circadian oscillator formation remains unknown. In differentiated somatic cells, the transcriptional-translational feedback loops (TTFL) consisting of clock genes elicit the molecular circadian oscillation. Using a bioluminescence imaging system to monitor clock gene expression, we show here that the circadian bioluminescence rhythm is not detected in the mouse embryonic stem (ES) cells, and that the ES cells likely lack TTFL regulation for clock gene expression. The circadian clock oscillation was induced during the differentiation culture of mouse ES cells without maternal factors. In addition, reprogramming of the differentiated cells by expression of Sox2, Klf4, Oct3/4, and c-Myc genes, which were factors to generate induced pluripotent stem (iPS) cells, resulted in the re-disappearance of circadian oscillation. These results demonstrate that an intrinsic program controls the formation of the circadian oscillator during the differentiation process of ES cells in vitro. The cellular differentiation and reprogramming system using cultured ES cells allows us to observe the circadian clock formation process and may help design new strategies to understand the key mechanisms responsible for the organization of the molecular oscillator in mammals.

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Development of the circadian oscillator during differentiation of mouse embryonic stem cells in vitro

Abstract

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