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WIREs Dev Biol
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Oscillatory gene expression and somitogenesis

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A bilateral pair of somites forms periodically by segmentation of the anterior ends of the presomitic mesoderm (PSM). This periodic event is regulated by a biological clock called the segmentation clock, which involves cyclic gene expression. Expression of her1 and her7 in zebrafish and Hes7 in mice oscillates by negative feedback, and mathematical models have been used to generate and test hypotheses to aide elucidation of the role of negative feedback in regulating oscillatory expression. her/Hes genes induce oscillatory expression of the Notch ligand deltaC in zebrafish and the Notch modulator Lunatic fringe in mice, which lead to synchronization of oscillatory gene expression between neighboring PSM cells. In the mouse PSM, Hes7 induces coupled oscillations of Notch and Fgf signaling, while Notch and Fgf signaling cooperatively regulate Hes7 oscillation, indicating that Hes7 and Notch and Fgf signaling form the oscillator networks. Notch signaling activates, but Fgf signaling represses, expression of the master regulator for somitogenesis Mesp2, and coupled oscillations in Notch and Fgf signaling dissociate in the anterior PSM, which allows Notch signaling‐induced synchronized cells to express Mesp2 after these cells are freed from Fgf signaling. These results together suggest that Notch signaling defines the prospective somite region, while Fgf signaling regulates the pace of segmentation. It is likely that these oscillator networks constitute the core of the segmentation clock, but it remains to be determined whether as yet unknown oscillators function behind the scenes. WIREs Dev Biol 2012 doi: 10.1002/wdev.46

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Figure 1.

Oscillatory expression of Hes7 in the presomitic mesoderm (PSM) during somite segmentation. (a) The anterior ends of the PSM are segmented every 2 h in mouse embryos, forming a bilateral pair of somites (Movie S1). In each cycle, Hes7 expression is initiated in the posterior end of the PSM (phase I) and is propagated into the anterior region (phase II), stopping near the anterior end (phase III). This dynamic expression is due to oscillatory expression in individual PSM cells (indicated by blue and green). (b) Spatiotemporal profiles of Hes7 expression.22 The x axis represents time, while the y axis represents space. The positions of somites are fixed, and the PSM grows posteriorly. (c) The vertebral column and ribs of wild‐type (WT) and Hes7 knockout (KO) embryos. The vertebral column and ribs of Hes7 KO mice are severely fused.

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Figure 2.

Hes7 oscillations regulated by negative feedback. Activation of the Hes7 promoter by Fgf and Notch signaling induces synthesis of both Hes7 mRNA and Hes7 protein. The Hes7 protein then forms a dimer, binds to multiple N box sequences of the Hes7 promoter and represses its own expression. This repression leads to disappearance of Hes7 mRNA and Hes7 protein because they are extremely unstable. Disappearance of Hes7 protein relieves negative auto‐regulation, allowing the next round of expression. As a result, Hes7 expression oscillates in the presomitic mesoderm.

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Figure 3.

Dynamics of Hes7 expression in the mouse presomitic mesoderm. (a) Hes7 gene transcription and Hes7 protein expression occur in a mutually exclusive manner in all three phases, indicating that Hes7 gene transcription is repressed by Hes7 protein. Arrow indicates a newly formed boundary. (b) Time course of Hes7 gene transcription, formation of Hes7 mRNA and formation of Hes7 protein.12 Hes7 gene transcription and Hes7 protein expression oscillate in an anti‐phase manner.

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Figure 4.

Mathematical model and its evaluation of Hes7 oscillation. (a) Mathematical simulation of Hes7 oscillations. According to the mathematical simulations,18 Hes7 oscillations continue to occur with the parameters set as 20 min for the Hes7 protein half‐life and 29 min for the transcriptional delay. (b) When the half‐life of Hes7 protein is 30 min, Hes7 oscillations are dampened down after three or four cycles. This defect is very similar to that of the Hes7 K14R mutation. (c) When the transcriptional delay is set as 10 min (19 min shorter than the wild type), Hes7 oscillations are abolished. This defect is very similar to that of Hes7 intronless (ΔIn) mice. (d) Uncx4.1 expression was analyzed by in situ hybridization in wild‐type, K14R mutant and Hes7 KO (knockout) mice at the eighth somite stage. The half‐life of the wild‐type Hes7 protein is about 20 min, while that of the Hes7 protein with the K14R mutation (the 14th amino acid residue lysine changed to arginine) is about 30 min. In mice expressing Hes7 with the K14R mutation, the initial three or four pairs of somites were segmented, but the subsequent somites were severely fused, indicating that Hes7 oscillations were dampened down after three or four cycles.18 All somites were segmented in wild‐type mice but were severely fused in Hes7 KO mice. (e) Uncx4.1 expression was analyzed by in situ hybridization in wild‐type and Hes7 intronless embryos. Intronic delay for mouse Hes7 expression is about 19–20 min, and without such a delay, Hes7 oscillation should be abolished according to the mathematical simulations.22 In intron‐less Hes7 mice, Hes7 expression does not oscillate, leading to segmentation defects.22

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Figure 5.

Notch signaling‐dependent synchronization between presomitic mesoderm (PSM) cells. (a) In zebrafish, expression of the Notch ligand DeltaC protein oscillates under the control of her1/her7 oscillations, and DeltaC oscillation seems to drive synchronization by periodic activation of Notch signaling. (b) In mice, Hes7 oscillations induce oscillatory expression of Lfng, which in turn leads to synchronization between neighboring cells by modulating Notch signaling activities.

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Figure 6.

Hes7‐mediated coupled oscillations in Fgf and Notch signaling in the segmentation clock. Hes7 oscillation induces oscillatory expression of Dusp4, a phosphatase induced by Fgf signaling, by periodic repression. Fgf signaling activates ERK by phosphorylation, and phosphorylated ERK (pERK) induces Hes7 and Dusp4 expression, while Dusp4 oscillation induces pERK oscillation. Hes7 oscillation also periodically represses Lfng. Lfng acts as an inhibitor of Notch signaling in the presomitic mesoderm (PSM), and therefore Lfng oscillations lead to oscillating formation of Notch intracellular domain (NICD), which in turn induces Hes7 and Lfng expression. Thus, pERK‐Dusp4 and Lfng‐NICD oscillations are coupled by Hes7 oscillations. Conversely, Hes7 oscillations are initiated by Fgf signaling in the posterior PSM and then amplified and propagated into the anterior PSM by Notch signaling. The coupled oscillator networks comprising Hes7, pERK‐Dusp4 and Lfng‐NICD underlie the segmentation clock.

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Figure 7.

Dynamic expression of Hes7, Notch intracellular domain (NICD), phosphorylated ERK (pERK) and Mesp2. (a) The posterior NICD domain moves anteriorly and narrows, while the pERK domain expands anteriorly, covering the NICD domain (middle two panels). After segmentation, pERK expression is downregulated, and NICD now induces Mesp2 expression in the S‐1 region (panel furthest to the right). Thus, oscillations in Notch signaling periodically segregate a group of synchronized cells, and oscillations in Fgf signaling release these synchronized cells for somitogenesis at the same time.21 (b) Schematic representation of spatiotemporal patterns of NICD, pERK and Mesp2 expression in the wild type.21 pERK expression displays an on‐off pattern, and Mesp2 expression is initiated periodically by NICD in the whole S‐1 region after pERK expression disappears. (c) Schematic representation of spatiotemporal patterns of NICD, pERK and Mesp2 expression in Hes7 KO (knockout) mice.21 In Hes7 KO mice, pERK expression steadily regresses posteriorly, and Mesp2 expression also steadily regresses in the anterior presomitic mesoderm (PSM) after Fgf/ERK signaling is turned off. Thus, Mesp2 expression is not periodic in Hes7 KO mice, indicating that the onset of Mesp2 expression occurs at different time between the anterior and posterior cells even in the same prospective somites. The PSM grows caudally (downward).

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