Setting the Tempo in Development: An Investigation of the Zebrafish Somite Clock Mechanism

Giudicelli, François; Özbudak, Ertuğrul M.; Wright, Gavin J.; Lewis, Julian

doi:10.1371/journal.pbio.0050150

Cited by 169 publications

(329 citation statements)

References 51 publications

(53 reference statements)

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“…These results suggest that the introns caused an ∼19-min delay in Hes7 expression, which was within the expected range of in vivo splicing kinetics (21,22). The ratio of this delay to the segmentation period is comparable to that of zebrafish (23).…”

Section: Resultssupporting

confidence: 68%

Intronic delay is essential for oscillatory expression in the segmentation clock

Takashima

Ohtsuka

González

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

160

169

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Proper timing of gene expression is essential for many biological events, but the molecular mechanisms that control timing remain largely unclear. It has been suggested that introns contribute to the timing mechanisms of gene expression, but this hypothesis has not been tested with natural genes. One of the best systems for examining the significance of introns is the oscillator network in the somite segmentation clock, because mathematical modeling predicted that oscillating expression depends on negative feedback with a delayed timing. The basic helix-loop-helix repressor gene Hes7 is cyclically expressed in the presomitic mesoderm (PSM) and regulates the somite segmentation. Here, we found that introns lead to an ∼19-min delay in the Hes7 gene expression, and mathematical modeling suggested that without such a delay, Hes7 oscillations would be abolished. To test this prediction, we generated mice carrying the Hes7 locus whose introns were removed. In these mice, Hes7 expression did not oscillate but occurred steadily, leading to severe segmentation defects. These results indicate that introns are indeed required for Hes7 oscillations and point to the significance of intronic delays in dynamic gene expression.

show abstract

Section: Resultssupporting

confidence: 68%

Intronic delay is essential for oscillatory expression in the segmentation clock

Takashima

Ohtsuka

González

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

160

169

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“…1D shows the regulatory network of the her segmentation clock gene in zebrafish. Her protein suppresses the transcription of her and delta mRNA (6,30). This negative feedback causes oscillatory expression of the her gene (6,8,30).…”

Section: Modelmentioning

confidence: 99%

“…Her protein suppresses the transcription of her and delta mRNA (6,30). This negative feedback causes oscillatory expression of the her gene (6,8,30). Each cell interacts with neighboring cells through Delta-Notch signaling, which activates her gene transcription (6,30).…”

Section: Modelmentioning

confidence: 99%

“…This negative feedback causes oscillatory expression of the her gene (6,8,30). Each cell interacts with neighboring cells through Delta-Notch signaling, which activates her gene transcription (6,30). We modeled the dynamics of her mRNA, Her protein in cytoplasm, Her protein in nucleus, and Delta protein explicitly (Eq.…”

Section: Modelmentioning

confidence: 99%

“…The oscillatory expression of the segmentation clock genes is known to be caused by the negative feedback regulation by their own products (6)(7)(8). Neighboring cells are in contact with each other (9,10).…”

mentioning

confidence: 99%

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Random cell movement promotes synchronization of the segmentation clock

Uriu

Morishita

Iwasa

2010

Proc. Natl. Acad. Sci. U.S.A.

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In vertebrate somitogenesis, the expression of segmentation clock genes oscillates and the oscillation is synchronized over nearby cells. Both experimental and theoretical studies have shown that the synchronization among cells is realized by intercellular interaction via Delta-Notch signaling. However, the following questions emerge: (i) During somitogenesis, dynamic rearrangement of relative cell positions is observed in the posterior presomitic mesoderm. Can a synchronized state be stably sustained under random cell movement? (ii) Experimental studies have reported that the synchronization of cells can be recovered in about 10 or fewer oscillation cycles after the complete loss of synchrony. However, such a quick recovery of synchronization is not possible according to previous theoretical models. In this paper, we first show by numerical modeling that synchronized oscillation can be sustained under random cell movement. We also find that for initial perturbation, the synchronization of cells is recovered much faster and it is for a wider range of reaction parameters than the case without cell movement. When the posterior presomitic mesoderm is rectangular, faster synchronization is achieved if cells exchange their locations more with neighbors located along the longer side of the domain. Finally, we discuss that the enhancement of synchronization by random cell movement occurs in several different models for the oscillation of segmentation clock genes.zebrafish | somitogenesis | Delta-Notch | mathematical models I n vertebrate development, somites bud off from the anterior end of the tissue not yet differentiated to somites, called the presomitic mesoderm (PSM), one by one moving posteriorly. The time interval between the formation of one somite and the next is almost constant during somitogenesis, and it is species-specific. In the PSM, there are segmentation clock genes with oscillating expression, and the timing of segmentation is considered to be controlled by the oscillatory expression of these genes because their period of oscillation is very close to the period of segmentation (1-5).The oscillatory expression of the segmentation clock genes is known to be caused by the negative feedback regulation by their own products (6-8). Neighboring cells are in contact with each other (9, 10). In the PSM, oscillatory expressions are synchronized among neighboring cells. This synchronized oscillation is necessary for normal segmentation, and disruption of the synchronization results in a defective somite boundary (11-13).Theoretical models of segmentation in vertebrates have been developed to explain the spatiotemporal periodicity of the segmentation process (14-18), the oscillatory expression of segmentation clock genes (19)(20)(21)(22)(23)(24), and the wave-like gene expression observed in the anterior PSM (23,(25)(26)(27)(28)(29). Previous theoretical studies have also addressed mechanisms of synchronization of the segmentation clock between cells (13,24,25,30). In zebrafish, the synchronization of the segment...

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Deadenylation by the CCR4‐NOT complex contributes to the turnover of hairy‐related mRNAs in the zebrafish segmentation clock

et al. 2018

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In the zebrafish segmentation clock, hairy/enhancer of split‐related genes her1, her7, and hes6 encodes components of core oscillators. Since the expression of cyclic genes proceeds rapidly in the presomitic mesoderm (PSM), these hairy‐related mRNAs are subject to strict post‐transcriptional regulation. In this study, we demonstrate that inhibition of the CCR4‐NOT deadenylase complex lengthens poly(A) tails of hairy‐related mRNAs and increases the amount of these mRNAs, which is accompanied by defective somite segmentation. In transgenic embryos, we show that EGFP mRNAs with 3′UTRs of hairy‐related genes exhibit turnover similar to endogenous mRNAs. Our results suggest that turnover rates of her1, her7, and hes6 mRNAs are differently regulated by the CCR4‐NOT deadenylase complex possibly through their 3′UTRs in the zebrafish PSM.

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Setting the Tempo in Development: An Investigation of the Zebrafish Somite Clock Mechanism

Cited by 169 publications

References 51 publications

Intronic delay is essential for oscillatory expression in the segmentation clock

Intronic delay is essential for oscillatory expression in the segmentation clock

Random cell movement promotes synchronization of the segmentation clock

Deadenylation by the CCR4‐NOT complex contributes to the turnover of hairy‐related mRNAs in the zebrafish segmentation clock

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