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Somitogenesis
Vertebrate body includes segmental structures such as vertebrae and ribs. These segmental structures are derived from mesodermal tissues called somites during development. Somites are formed one by one from the head to the tail in a species-specific temporal period (5 hours for human, 2 hours for mouse, 1.5 hours for chick, and 0.5 hours for zebrafish). It has been known that the period of segment formation is determined by the oscillation of protein concentrations in cells. This oscillation acts as a "clock" that determines the timing of somite formation, and is known as a "segmentation clock”. Cells communicate with neighboring cells to synchronize the segmentation clock (protein rhythms) to differentiate into a somite at the same time.
Cell movement and synchronization of segmentation clock
Somites bud off from the anterior part of an unsegmented tissue, the presomitic mesoderm. Each cell can communicate with neighboring cells with membrane proteins, Delta ligands and Notch receptors. In addition, cells in the presomitic mesoderm move around in the tissue, exchanging neighboring cells over time. How do cells synchronize segmentation clock if they move and frequently exchange their neighbors to communicate?
To answer this question, we choose a theoretical approach; we quantified cell movement by tracking cells in imaging data, and simulated cell movement on a computer. We found that cell movement and neighbor exchange promote synchronization of the segmentation clock. The synchronization with neighboring cells is indeed disrupted by movement. However, movement also creates a chance to communicate with cells that were previously distant. Therefore, at a cell population level, cell movement facilitates information transfer, realizing quick synchronization. Our study suggests that cell movement allows for robust somite formation in development.
Uriu K., Bhavna R., Oates A.C., Morelli L.G. (2017) A framework for quantification and physical modeling of cell mixing applied to oscillator synchronization in vertebrate somitogenesis. Biol. Open 6 1235-1244
Resynchronization of segmentation clock
The shape of presomitic mesoderm changes (deformation) during somitogenesis. To clarify the effect of this tissue deformation on the spatiotemporal dynamics of the segmentation clock, we analyzed the resynchronization process of the zebrafish segmentation clock using a mathematical modeling and imaging data.
We used an inhibitor of Delta-Notch signaling to desynchronize the segmentation clock between cells. Subsequently, we removed the inhibitor and restored cell-cell interactions. The segmentation clock resynchronizes over time, and we simulated this process using a mathematical model. We found that the way the segmentation clock resynchronizes depends on how the tissue is deformed. We also confirmed that predictions of simulations were consistent with experimental data.
Uriu K., Liao B-K, Oates A.C., Morelli L.G. (2021) From local resynchronization to global pattern recovery in the zebrafish segmentation clock. eLife 10 e61358
Circadian clock
Almost all living organisms, including humans, have an internal clock that measures 24-hour cycles, known as the circadian clock. The circadian clocks regulate behavioral and physiological rhythms with nearly 24-hour period in these organisms. In humans, the pacemaker of the circadian clock is located in the brain tissue suprachiasmatic nucleus (SCN), which consists of tens of thousands of neurons. In these neurons, expression of circadian clock genes oscillates in approximately 24-hour period. In mammals, several circadian clock genes such as Period (Per), Cryptochrome (Cry), Bmal1, and Clock have been identified. Regulatory network of these circadian clock genes is the basis for the generation of transcriptional rhythms. For example, in mammals, the CLOCK-BMAL1 complex induces transcription of Per and Cry. Translated PER and CRY protein then form complex and repress the transcriptional activity of CLOCK-BMAL1. This negative feedback regulation by Per and Cry is essential for generating circadian rhythms.
Light input from the retina is transmitted to the SCN and alters the gene expression rhythms in SCN neurons. Depending on the time of day when the light stimulus is received, the expression rhythm of circadian clock gene is either advanced or delayed. This allows the circadian clock to entrain to the light-dark cycle, so that, for example, when we travel abroad, we can adjust our circadian clock to the local time within a few days.
Different roles of Per1 and Per2 in phase response
Light information is input to two circadian clock genes, Per1 and Per2. Because of the homology of amino acid sequences between PER1 and PER2 proteins, we would expect that these two proteins have similar functions. Are Per1 and Per2 simply two redundant circadian clock genes with the same function? There is a phase difference between the expression rhythms of Per1 and Per2, with Per2 expression peaking about 4 hours after the peak of Per1 transcription. We have shown by mathematical modeling that this 4-hour time difference results in distinct roles in the light response; Per1 advances the circadian clock upon light stimulation, while Per2 delays it. These results suggest that if, for example, a compound that specifically induces the transcription of only Per1 is identified, the circadian clock can be advanced independently of administration timing. Such a compound would have potential as a therapeutic agent for jet lag and sleep disorders.
Uriu K., Tei H. (2021) Complementary phase responses via functional differentiation of dual negative feedback loops. PLOS Comp. Biol. 17 e1008774
Dead zone of circadian clock
In many organisms, the phase of the circadian clock does not change when exposed to light during the organism's subjective daytime. This refractory period is called the dead zone. Although previous studies have shown that the presence of a dead zone makes the circadian clock more accurate, it was unclear how the dead zone is formed.
We theoretically investigated the mechanism of the dead zone formation at the single-cell level by calculating the phase sensitivity of limit cycles. We found that a dead zone is generated when the reaction in synthesis of repressors in the negative feedback loop is saturated.
Which reaction should be saturated depends on how the molecular network of circadian clock responds to light signals. A dead zone appears when repressor transcription is saturated in Drosophila. On the other hand, in mammals and the Neurospora, the mathematical model predicts that the dead zone is formed when translation of the repressor is saturated.
Uriu K., Tei H. (2019) A saturated reaction in repressor synthesis creates a daytime dead zone in circadian clocks. PLOS Compt. Biol. 15 e1006787
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