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Circadian key component CLOCK/BMAL1 interferes with segmentation clock in mouse embryonic organoids
Yasuhiro Umemura1, Nobuya Koike1, Yoshiki Tsuchiya1
1Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Abstract:
In mammals, circadian clocks are strictly suppressed during early embryonic stages, as well as in pluripotent stem cells, by the lack of CLOCK/BMAL1-mediated circadian feedback loops. During ontogenesis, the innate circadian clocks emerge gradually at a late developmental stage, and with these, the circadian temporal order is invested in each cell level throughout a body. Meanwhile, in the early developmental stage, a segmented body plan is essential for an intact developmental process, and somitogenesis is controlled by another cell-autonomous oscillator, the segmentation clock, in the posterior presomitic mesoderm (PSM). In the present study, focusing upon the interaction between circadian key components and the segmentation clock, we investigated the effect of the CLOCK/BMAL1 on the segmentation clock Hes7 oscillation, revealing that the expression of functional CLOCK/BMAL1 severely interferes with the ultradian rhythm of segmentation clock in induced PSM and gastruloids. RNA sequencing analysis implied that the premature expression of CLOCK/BMAL1 affects the Hes7 transcription and its regulatory pathways. These results suggest that the suppression of CLOCK/BMAL1-mediated transcriptional regulation during the somitogenesis may be inevitable for intact mammalian development.
Insights
Mammalian embryonic development requires suppressing circadian clock components, CLOCK/BMAL1, to allow proper somitogenesis. Their premature expression disrupts the segmentation clock, highlighting their essential role in early development.
Area of Science:
- Developmental Biology
- Chronobiology
- Molecular Biology
Background:
- Mammalian embryonic development involves precise temporal regulation, with circadian clocks emerging late.
- Early development relies on the segmentation clock for body plan formation in the posterior presomitic mesoderm.
- Circadian regulators like CLOCK/BMAL1 are suppressed during early embryonic stages.
Purpose of the Study:
- To investigate the interaction between circadian clock components (CLOCK/BMAL1) and the segmentation clock.
- To determine the effect of CLOCK/BMAL1 on the segmentation clock's Hes7 oscillation.
- To understand the implications of premature CLOCK/BMAL1 expression on embryonic development.
Main Methods:
- Utilizing induced posterior presomitic mesoderm (iPSM) and gastruloids.
- Analyzing Hes7 oscillation in the presence of functional CLOCK/BMAL1.
- Performing RNA sequencing to assess transcriptional changes.
Main Results:
- Functional CLOCK/BMAL1 severely interferes with the ultradian rhythm of the segmentation clock.
- Premature CLOCK/BMAL1 expression disrupts Hes7 transcription and its regulatory pathways.
- These disruptions were observed in both induced PSM and gastruloid models.
Conclusions:
- Suppression of CLOCK/BMAL1-mediated transcription is crucial for intact mammalian somitogenesis.
- The segmentation clock's rhythm is sensitive to the early presence of circadian regulators.
- This suggests a necessary temporal separation between circadian clock establishment and early body plan formation.
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