The vertebrate segmentation clock drives segmentation by stabilizing Dusp phosphatases
Ontology highlight
ABSTRACT:
ORGANISM(S): Danio rerio (zebrafish)
SUBMITTER:
PROVIDER: S-BSST1653 | biostudies-other |
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Gene expression is an inherently stochastic process1,2; however, organismal development and homeostasis require cells to coordinate the spatiotemporal expression of large sets of genes. In metazoans, pairs of co-expressed genes often reside in the same chromosomal neighbourhood, with gene pairs representing 10 to 50% of all genes, depending on the species3-6. Because shared upstream regulators can ensure correlated gene expression, the selective advantage of maintaining adjacent gene pairs remains unknown6. Here, using two linked zebrafish segmentation clock genes, her1 and her7, and combining single-cell transcript counting, genetic engineering, real-time imaging and computational modelling, we show that gene pairing boosts correlated transcription and provides phenotypic robustness for the formation of developmental patterns. Our results demonstrate that the prevention of gene pairing disrupts oscillations and segmentation, and the linkage of her1 and her7 is essential for the development of the body axis in zebrafish embryos. We predict that gene pairing may be similarly advantageous in other organisms, and our findings could lead to the engineering of precise synthetic clocks in embryos and organoids.
| S-EPMC7932681 | biostudies-literature
Project description:Sequential production of body segments in vertebrate embryos is regulated by a molecular oscillator (the segmentation clock) that drives cyclic transcription of genes involved in positioning intersegmental boundaries. Mathematical modeling indicates that the period of the clock depends on the total delay kinetics of a negative feedback circuit, including those associated with the synthesis of transcripts encoding clock components [Lewis J (2003) Curr Biol 13(16):1398-1408]. Here, we measure expression delays for three transcripts [Lunatic fringe, Hes7/her1, and Notch-regulated-ankyrin-repeat-protein (Nrarp)], that cycle during segmentation in the zebrafish, chick, and mouse, and provide in vivo measurements of endogenous splicing and export kinetics. We show that mRNA splicing and export are much slower than transcript elongation, with the longest delay (about 16 min in the mouse) being due to mRNA export. We conclude that the kinetics of mRNA and protein production and destruction can account for much of the clock period, and provide strong support for delayed autorepression as the underlying mechanism of the segmentation clock.
| S-EPMC3831944 | biostudies-literature
Project description:Biological timekeeping is determined by internal temporal programmes and the resetting of these programmes or clocks by external stimuli. Many of the core genes of the mammalian daily or circadian clock are known, but the factors regulating so-called 'clock' gene proteins are unclear. In this issue of the Biochemical Journal, Gallego and colleagues show for the first time that protein phosphatase 1 plays a major role in the stability of mammalian PER2, a key protein in the core clock works. This contrasts somewhat with circadian rhythm control in the fruitfly Drosophila and the fungus Neurospora where current evidence supports a role for protein phosphatase 2A in core timekeeping. The mechanisms underpinning these actions of phosphatase 1 are unclear, and future investigations will need to identify the regulatory subunit that targets phosphatase 1 to mammalian PER2 (Period 2).
| S-EPMC1570164 | biostudies-other
Project description:Taming cell-to-cell variability in gene expression is critical for precise pattern formation during embryonic development. To investigate the source and buffering mechanism of expression variability, we studied a biological clock, the vertebrate segmentation clock, controlling the precise spatiotemporal patterning of the vertebral column. By counting single transcripts of segmentation clock genes in zebrafish, we show that clock genes have low RNA amplitudes and expression variability is primarily driven by gene extrinsic sources, which is suppressed by Notch signaling. We further show that expression noise surprisingly increases from the posterior progenitor zone to the anterior segmentation and differentiation zone. Our computational model reproduces the spatial noise profile by incorporating spatially increasing time delays in gene expression. Our results, suggesting that expression variability is controlled by the balance of time delays and cell signaling in a vertebrate tissue, will shed light on the accuracy of natural clocks in multi-cellular systems and inspire engineering of robust synthetic oscillators.
| S-EPMC5989725 | biostudies-literature
Project description:Rhythmic and sequential subdivision of the elongating vertebrate embryonic body axis into morphological somites is controlled by an oscillating multicellular genetic network termed the segmentation clock. This clock operates in the presomitic mesoderm (PSM), generating dynamic stripe patterns of oscillatory gene-expression across the field of PSM cells. How these spatial patterns, the clock's collective period, and the underlying cellular-level interactions are related is not understood. A theory encompassing temporal and spatial domains of local and collective aspects of the system is essential to tackle these questions. Our delayed coupling theory achieves this by representing the PSM as an array of phase oscillators, combining four key elements: a frequency profile of oscillators slowing across the PSM; coupling between neighboring oscillators; delay in coupling; and a moving boundary describing embryonic axis elongation. This theory predicts that the segmentation clock's collective period depends on delayed coupling. We derive an expression for pattern wavelength across the PSM and show how this can be used to fit dynamic wildtype gene-expression patterns, revealing the quantitative values of parameters controlling spatial and temporal organization of the oscillators in the system. Our theory can be used to analyze experimental perturbations, thereby identifying roles of genes involved in segmentation.
| S-EPMC2689616 | biostudies-literature
Project description:Receptor-type protein tyrosine phosphatases (RPTPs) are required for appropriate growth of axons during nervous system development in Drosophila. In the vertebrate, type IIa RPTPs [protein tyrosine phosphatase (PTP)-delta, PTP-sigma, and LAR (leukocyte common-antigen-related)] and the type III RPTP, PTP receptor type O (PTPRO), have been implicated in the regulation of axon growth, but their roles in developmental axon guidance are unclear. PTPRO, PTP-delta, and PTP-sigma are each expressed in chick motor neurons during the period of axonogenesis. To examine potential roles of RPTPs in axon growth and guidance in vivo, we used double-stranded RNA (dsRNA) interference combined with in ovo electroporation to knock down RPTP expression levels in the embryonic chick lumbar spinal cord. Although most branches of the developing limb nerves appeared grossly normal, a dorsal nerve identified as the anterior iliotibialis was clearly affected by dsRNA knock-down of RPTPs. In experimental embryos treated with dsRNA targeting PTP-delta, PTP-sigma, or PTPRO, this nerve showed abnormal fasciculation, was reduced in size, or was missing entirely; interference with PTPRO produced the most severe phenotypes. Control embryos electroporated with vehicle, or with dsRNA targeting choline acetyltransferase or axonin-1, did not exhibit this phenotype. Surprisingly, embryos electroporated with dsRNA targeting PTP-delta together with PTPRO, or all three RPTPs combined, had less severe phenotypes than embryos treated with PTPRO alone. This result suggests that competition between type IIa and type III RPTPs can regulate motor axon outgrowth, consistent with findings in Drosophila. Our results indicate that RPTPs, and especially PTPRO, are required for axon growth and guidance in the developing vertebrate limb.
| S-EPMC6724933 | biostudies-literature
Project description:The vertebral column is a conserved anatomical structure that defines the vertebrate phylum. The periodic or segmental pattern of the vertebral column is established early in development when the vertebral precursors, the somites, are rhythmically produced from presomitic mesoderm (PSM). This rhythmic activity is controlled by a segmentation clock that is associated with the periodic transcription of cyclic genes in the PSM. Comparison of the mouse, chicken and zebrafish PSM oscillatory transcriptomes revealed networks of 40 to 100 cyclic genes mostly involved in Notch, Wnt and FGF signaling pathways. However, despite this conserved signaling oscillation, the identity of individual cyclic genes mostly differed between the three species, indicating a surprising evolutionary plasticity of the segmentation networks.
| S-EPMC3109603 | biostudies-literature
Project description:The segmental organization of the vertebral column is established early in embryogenesis when pairs of somites are rhythmically produced by the presomitic mesoderm (PSM). The tempo of somite formation is controlled by a molecular oscillator known as the segmentation clock. While this oscillator has been well-characterized in model organisms, whether a similar oscillator exists in humans remains unknown. Genetic analysis of patients with severe spine segmentation defects have implicated several human orthologs of cyclic genes associated with the mouse segmentation clock, suggesting that this oscillator might be conserved in humans. Here we show that in vitro-derived human as well as mouse PSM cells recapitulate oscillations of the segmentation clock. Human PSM cells oscillate twice slower than mouse cells (5-hours vs. 2.5 hours), but are similarly regulated by FGF, Wnt, Notch and YAP. Single cell RNA-sequencing reveals that mouse and human PSM cells in vitro follow a similar developmental trajectory to mouse PSM in vivo. Furthermore, we demonstrate that FGF signaling controls the phase and period of oscillations, expanding the role of this pathway beyond its classical interpretation in 'Clock and Wavefront' models. Overall, our work identifying the human segmentation clock represents an important breakthrough for human developmental biology.
2019-10-28 | GSE114186 | GEO
Project description:Selective and/or neutral processes may govern variation in DNA content and, ultimately, genome size. The observation in several organisms of a negative correlation between recombination rate and intron size could be compatible with a neutral model in which recombination is mutagenic for length changes. We used whole-genome data on small insertions and deletions within transposable elements from chicken and zebra finch to demonstrate clear links between recombination rate and a number of attributes of reduced DNA content. Recombination rate was negatively correlated with the length of introns, transposable elements, and intergenic spacer and with the rate of short insertions. Importantly, it was positively correlated with gene density, the rate of short deletions, the deletion bias, and the net change in sequence length. All these observations point at a pattern of more condensed genome structure in regions of high recombination. Based on the observed rates of small insertions and deletions and assuming that these rates are representative for the whole genome, we estimate that the genome of the most recent common ancestor of birds and lizards has lost nearly 20% of its DNA content up until the present. Expansion of transposable elements can counteract the effect of deletions in an equilibrium mutation model; however, since the activity of transposable elements has been low in the avian lineage, the deletion bias is likely to have had a significant effect on genome size evolution in dinosaurs and birds, contributing to the maintenance of a small genome. We also demonstrate that most of the observed correlations between recombination rate and genome contraction parameters are seen in the human genome, including for segregating indel polymorphisms. Our data are compatible with a neutral model in which recombination drives vertebrate genome size evolution and gives no direct support for a role of natural selection in this process.
| S-EPMC3342960 | biostudies-literature
Project description:In mammals, circadian clocks are strictly suppressed during early embryonic stages as well as 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, then, with which 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 showed 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.
2021-12-09 | GSE181295 | GEO