期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：1
DOI：10.1073/pnas.2114083119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Although the circadian clock is essential for regulating the temporal order of physiological functions, circadian oscillation is strictly suppressed in the early-to-mid–stage embryos in mammalian developmental process. The biological significance controlling the suppression of the circadian clock and its delayed emergence in mammalian embryos has been unknown. Here, we show that the premature expression of the functional circadian components CLOCK/BMAL1 in mouse induced presomitic mesoderm and gastruloids can interfere with the segmentation clock
Hes7 oscillation and somitogenesis through the
Hes7 transcription and its regulatory pathways. This suggests that the CLOCK/BMAL1 function may need to be suppressed during somitogenesis.
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.
