Talk:Somitogenesis
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Cite this page: Hill, M.A. (2024, April 27) Embryology Somitogenesis. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Somitogenesis |
2020
Yoshioka-Kobayashi K, Matsumiya M, Niino Y, Isomura A, Kori H, Miyawaki A & Kageyama R. (2020). Coupling delay controls synchronized oscillation in the segmentation clock. Nature , , . PMID: 31915376 DOI.
Coupling delay controls synchronized oscillation in the segmentation clock.
Abstract Individual cellular activities fluctuate but are constantly coordinated at the population level via cell-cell coupling. A notable example is the somite segmentation clock, in which the expression of clock genes (such as Hes7) oscillates in synchrony between the cells that comprise the presomitic mesoderm (PSM)1,2. This synchronization depends on the Notch signalling pathway; inhibiting this pathway desynchronizes oscillations, leading to somite fusion3-7. However, how Notch signalling regulates the synchronicity of HES7 oscillations is unknown. Here we establish a live-imaging system using a new fluorescent reporter (Achilles), which we fuse with HES7 to monitor synchronous oscillations in HES7 expression in the mouse PSM at a single-cell resolution. Wild-type cells can rapidly correct for phase fluctuations in HES7 oscillations, whereas the absence of the Notch modulator gene lunatic fringe (Lfng) leads to a loss of synchrony between PSM cells. Furthermore, HES7 oscillations are severely dampened in individual cells of Lfng-null PSM. However, when Lfng-null PSM cells were completely dissociated, the amplitude and periodicity of HES7 oscillations were almost normal, which suggests that LFNG is involved mostly in cell-cell coupling. Mixed cultures of control and Lfng-null PSM cells, and an optogenetic Notch signalling reporter assay, revealed that LFNG delays the signal-sending process of intercellular Notch signalling transmission. These results-together with mathematical modelling-raised the possibility that Lfng-null PSM cells shorten the coupling delay, thereby approaching a condition known as the oscillation or amplitude death of coupled oscillators8. Indeed, a small compound that lengthens the coupling delay partially rescues the amplitude and synchrony of HES7 oscillations in Lfng-null PSM cells. Our study reveals a delay control mechanism of the oscillatory networks involved in somite segmentation, and indicates that intercellular coupling with the correct delay is essential for synchronized oscillation. DOI: 10.1038/s41586-019-1882-z
Diaz-Cuadros M, Wagner DE, Budjan C, Hubaud A, Tarazona OA, Donelly S, Michaut A, Al Tanoury Z, Yoshioka-Kobayashi K, Niino Y, Kageyama R, Miyawaki A, Touboul J & Pourquié O. (2020). In vitro characterization of the human segmentation clock. Nature , , . PMID: 31915384 DOI.
In vitro characterization of the human segmentation clock.
Abstract 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 clock1,2. Although this oscillator has been well-characterized in model organisms1,2, whether a similar oscillator exists in humans remains unknown. Genetic analyses of patients with severe spine segmentation defects have implicated several human orthologues of cyclic genes that are associated with the mouse segmentation clock, suggesting that this oscillator might be conserved in humans3. Here we show that human PSM cells derived in vitro-as well as those of the mouse4-recapitulate the oscillations of the segmentation clock. Human PSM cells oscillate with a period two times longer than that of mouse cells (5 h versus 2.5 h), but are similarly regulated by FGF, WNT, Notch and YAP signalling5. Single-cell RNA sequencing reveals that mouse and human PSM cells in vitro follow a developmental trajectory similar to that of mouse PSM in vivo. Furthermore, we demonstrate that FGF signalling controls the phase and period of oscillations, expanding the role of this pathway beyond its classical interpretation in 'clock and wavefront' models1. Our work identifying the human segmentation clock represents an important milestone in understanding human developmental biology. DOI: 10.1038/s41586-019-1885-9
2019
Juul JS, Jensen MH & Krishna S. (2019). Constraints on somite formation in developing embryos. J R Soc Interface , 16, 20190451. PMID: 31530134 DOI.
Constraints on somite formation in developing embryos.
Abstract Segment formation in vertebrate embryos is a stunning example of biological self-organization. Here, we present an idealized framework, in which we treat the presomitic mesoderm (PSM) as a one-dimensional line of oscillators. We use the framework to derive constraints that connect the size of somites, and the timing of their formation, to the growth of the PSM and the gradient of the somitogenesis clock period across the PSM. Our analysis recapitulates the observations made recently in ex vivo cultures of mouse PSM cells, and makes predictions for how perturbations, such as increased Wnt levels, would alter somite widths. Finally, our analysis makes testable predictions for the shape of the phase profile and somite widths at different stages of PSM growth. In particular, we show that the phase profile is robustly concave when the PSM length is steady and slightly convex in an important special case when it is decreasing exponentially. In both cases, the phase profile scales with the PSM length; in the latter case, it scales dynamically. This has important consequences for the velocity of the waves that traverse the PSM and trigger somite formation, as well as the effect of errors in phase measurement on somite widths. KEYWORDS: dynamical scaling; oscillators; phase waves; scaling; somites PMID: 31530134 PMCID: PMC6769302 DOI: 10.1098/rsif.2019.0451
2017
Chicken
| Chicken Somitogenesis | ||
|---|---|---|
| 23-26 hr | 1 somite | |
| ca. 23-26 hr | 1-3 | |
| 26-29 hr | 4 | |
| 29-33 hr | 7 | |
| ca. 33 hr | 8-9 | |
| 33-38 hr | 10 | |
| 40-45 hr | 13 | |
| 45-49 hr | 16 | |
| 48-52 hr | 19 | |
| ca. 50-52 hr | 20-21 | |
| 50-53 hr | 22 | |
| ca. 50-54 hr | 23 | |
| 50-55 hr | 24-27 | |
| 51-56 hr | 26-28 | |
| 52-64 hr | 29-32 | |
| 3 da | 30-36 | |
| 3.0-3.5 da | 37- 40 extending into tail | |
| 3.0-3.5 da | 40-43 | |
| 3.5 da | 43-44 | |
| 3.5-4.0 da | Somites extend to tip of tail | |
| Hamburger Hamilton Stages | Chicken Development | ||
| Chicken Somitogenesis | ||
|---|---|---|
| 23-26 hr | 1 somite | |
| ca. 23-26 hr | 1-3 | |
| 26-29 hr | 4 | |
| 29-33 hr | 7 | |
| ca. 33 hr | 8-9 | |
| 33-38 hr | 10 | |
| 40-45 hr | 13 | |
| 45-49 hr | 16 | |
| 48-52 hr | 19 | |
| ca. 50-52 hr | 20-21 | |
| 50-53 hr | 22 | |
| ca. 50-54 hr | 23 | |
| 50-55 hr | 24-27 | |
| 51-56 hr | 26-28 | |
| 52-64 hr | 29-32 | |
| 3 da | 30-36 | |
| 3.0-3.5 da | 37- 40 extending into tail | |
| 3.0-3.5 da | 40-43 | |
| 3.5 da | 43-44 | |
| 3.5-4.0 da | Somites extend to tip of tail | |
| Hamburger Hamilton Stages | Chicken Development | ||
| Chicken Somitogenesis | ||
|---|---|---|
| 23-26 hr | 1 somite | |
| ca. 23-26 hr | 1-3 | |
| 26-29 hr | 4 | |
| 29-33 hr | 7 | |
| ca. 33 hr | 8-9 | |
| 33-38 hr | 10 | |
| 40-45 hr | 13 | |
| 45-49 hr | 16 | |
| 48-52 hr | 19 | |
| ca. 50-52 hr | 20-21 | |
| 50-53 hr | 22 | |
| ca. 50-54 hr | 23 | |
| 50-55 hr | 24-27 | |
| 51-56 hr | 26-28 | |
| 52-64 hr | 29-32 | |
| 3 da | 30-36 | |
| 3.0-3.5 da | 37- 40 extending into tail | |
| 3.0-3.5 da | 40-43 | |
| 3.5 da | 43-44 | |
| 3.5-4.0 da | Somites extend to tip of tail | |
| Hamburger Hamilton Stages | Chicken Development | ||
2016
Developmental dynamics of occipital and cervical somites
J Anat. 2016 Jul 6. doi: 10.1111/joa.12516. [Epub ahead of print]
Maschner A1, Krück S2, Draga M2, Pröls F2, Scaal M2,1.
Abstract
Development of somites leading to somite compartments, sclerotome, dermomyotome and myotome, has been intensely investigated. Most knowledge on somite development, including the commonly used somite maturation stages, is based on data from somites at thoracic and lumbar levels. Potential regional differences in somite maturation dynamics have been indicated by a number of studies, but have not yet been comprehensively examined. Here, we present an overview on the developmental dynamics of somites at occipital and cervical levels in the chicken embryo. We show that in these regions, the onset of sclerotomal and myotomal compartment formation is later than at thoracolumbar levels, and is initiated simultaneously in multiple somites, which is in contrast to the serial cranial- to- caudal progression of somite maturation in the trunk. Our data suggest a variant spatiotemporal regulation of somite development in occipitocervical somites. © 2016 Anatomical Society. KEYWORDS: MyoD ; Pax1 ; cervical; chicken embryo; myotome; occipital; sclerotome; somite PMID 27380812
Revisiting the involvement of signaling gradients in somitogenesis
FEBS J. 2016 Apr;283(8):1430-7. doi: 10.1111/febs.13622. Epub 2015 Dec 31.
Mallo M1.
Abstract
During embryonic development, formation of individual vertebrae requires that the paraxial mesoderm becomes divided into regular segmental units known as somites. Somites are sequentially formed at the anterior end of the presomitic mesoderm (PSM) resulting from functional interactions between the oscillatory activity of signals promoting segmentation and a moving wavefront of tissue competence to those signals, eventually generating a constant flow of new somites at regular intervals. According to the current model for somitogenesis, the wavefront results from the combined activity of two opposing functional gradients in the PSM involving the Fgf, Wnt and retinoic acid (RA) signaling pathways. Here, I use published data to evaluate the wavefront model. A critical analysis of those studies seems to support a role for Wnt signaling, but raise doubts regarding the extent to which Fgf and RA signaling contribute to this process. © 2015 FEBS. KEYWORDS: development; mesoderm; segmentation; signaling; somite formation; vertebrate
PMID 26662366
Different Concentrations of FGF Ligands, FGF2 or FGF8 Determine Distinct States of WNT-Induced Presomitic Mesoderm
Stem Cells. 2016 Apr 1. doi: 10.1002/stem.2371. [Epub ahead of print]
Sudheer S1, Liu J1, Marks M1, Koch F1, Anurin A1,2, Scholze M1, Dorothea Senft A1, Wittler L1, Macura K1, Grote P1, Herrmann BG1.
Abstract
Presomitic mesoderm (PSM; also called paraxial mesoderm) cells are the precursors of the somites, which flank both sides of the neural tube and give rise to the musculo-skeletal system shaping the vertebrate body. WNT and FGF signaling control the formation of both the PSM and the somites, and show a graded distribution with highest levels in the posterior PSM. We have employed reporters for the mesoderm/PSM control genes T, Tbx6 and Msgn1 to investigate the differentiation of mouse ESCs from the naïve state via EpiSCs to PSM cells. Here we show that the activation of WNT signaling by CHIR99021 (CH) in combination with FGF ligand induces embryo-like PSM at high efficiency. By varying the FGF ligand concentration, the state of PSM cells formed can be altered. High FGF concentration supports posterior PSM formation, whereas low FGF generates anterior/differentiating PSM, in line with in vivo data. Furthermore, the level of Msgn1 expression depends on the FGF ligand concentration. We also show that Activin/Nodal signaling inhibits CH-mediated PSM induction in EpiSCs, without affecting T-expression. Inversely, Activin/Nodal inhibition enhances PSM induction by WNT/high FGF signaling. The ability to generate PSM cells of either posterior or anterior PSM identity with high efficiency in vitro will promote the investigation of the gene regulatory networks controlling the formation of nascent PSM cells and their switch to differentiating/somitic paraxial mesoderm. This article is protected by copyright. All rights reserved. © 2016 AlphaMed Press. KEYWORDS: Brachyury; CHIR99021; Differentiation; Embryonic stem cells; EpiSCs; FGF; Mesogenin; Paraxial mesoderm; TBX6; WNT
PMID 27038343
2015
Dynamics of the slowing segmentation clock reveal alternating two-segment periodicity
Development. 2015 May 15;142(10):1785-93. doi: 10.1242/dev.119057.
Shih NP1, François P2, Delaune EA3, Amacher SL4.
Abstract
The formation of reiterated somites along the vertebrate body axis is controlled by the segmentation clock, a molecular oscillator expressed within presomitic mesoderm (PSM) cells. Although PSM cells oscillate autonomously, they coordinate with neighboring cells to generate a sweeping wave of cyclic gene expression through the PSM that has a periodicity equal to that of somite formation. The velocity of each wave slows as it moves anteriorly through the PSM, although the dynamics of clock slowing have not been well characterized. Here, we investigate segmentation clock dynamics in the anterior PSM in developing zebrafish embryos using an in vivo clock reporter, her1:her1-venus. The her1:her1-venus reporter has single-cell resolution, allowing us to follow segmentation clock oscillations in individual cells in real-time. By retrospectively tracking oscillations of future somite boundary cells, we find that clock reporter signal increases in anterior PSM cells and that the periodicity of reporter oscillations slows to about ∼1.5 times the periodicity in posterior PSM cells. This gradual slowing of the clock in the anterior PSM creates peaks of clock expression that are separated at a two-segment periodicity both spatially and temporally, a phenomenon we observe in single cells and in tissue-wide analyses. These results differ from previous predictions that clock oscillations stop or are stabilized in the anterior PSM. Instead, PSM cells oscillate until they incorporate into somites. Our findings suggest that the segmentation clock may signal somite formation using a phase gradient with a two-somite periodicity. © 2015. Published by The Company of Biologists Ltd. KEYWORDS: In vivo imaging; Oscillations; Segmentation clock; Somite; Two-segment periodicity; Zebrafish; her1
PMID 25968314
http://dev.biologists.org/content/142/10/1785.long
2014
Mesogenin 1 is a master regulator of paraxial presomitic mesoderm differentiation
Development. 2014 Nov;141(22):4285-97. doi: 10.1242/dev.110908.
Chalamalasetty RB1, Garriock RJ1, Dunty WC Jr1, Kennedy MW1, Jailwala P2, Si H2, Yamaguchi TP3.
Abstract
Neuromesodermal (NM) stem cells generate neural and paraxial presomitic mesoderm (PSM) cells, which are the respective progenitors of the spinal cord and musculoskeleton of the trunk and tail. The Wnt-regulated basic helix-loop-helix (bHLH) transcription factor mesogenin 1 (Msgn1) has been implicated as a cooperative regulator working in concert with T-box genes to control PSM formation in zebrafish, although the mechanism is unknown. We show here that, in mice, Msgn1 alone controls PSM differentiation by directly activating the transcriptional programs that define PSM identity, epithelial-mesenchymal transition, motility and segmentation. Forced expression of Msgn1 in NM stem cells in vivo reduced the contribution of their progeny to the neural tube, and dramatically expanded the unsegmented mesenchymal PSM while blocking somitogenesis and notochord differentiation. Expression of Msgn1 was sufficient to partially rescue PSM differentiation in Wnt3a(-/-) embryos, demonstrating that Msgn1 functions downstream of Wnt3a as the master regulator of PSM differentiation. Our data provide new insights into how cell fate decisions are imposed by the expression of a single transcriptional regulator. © 2014. Published by The Company of Biologists Ltd. KEYWORDS: Differentiation; EMT; Embryonic stem cell; Motility; Mouse; PSM; Paraxial mesoderm; Somite; Wnt; bHLH transcription factor
PMID 25371364
2013
The dermomyotome ventrolateral lip is essential for the hypaxial myotome formation
BMC Dev Biol. 2013 Oct 18;13:37. doi: 10.1186/1471-213X-13-37.
Pu Q1, Abduelmula A, Masyuk M, Theiss C, Schwandulla D, Hans M, Patel K, Brand-Saberi B, Huang R. Author information
Abstract
BACKGROUND: The myotome is the primitive skeletal muscle that forms within the embryonic metameric body wall. It can be subdivided into an epaxial and hypaxial domain. It has been shown that the formation of the epaxial myotome requires the dorsomedial lip of the dermomyotome (DML). Although the ventrolateral lip (VLL) of the dermomyotome is believed to be required for the formation of the hypaxial myotome, experimentally evidence for this statement still needs to be provided. Provision of such data would enable the resolution of a debate regarding the formation of the hypaxial dermomyotome. Two mechanisms have been proposed for this tissue. The first proposes that the intermediate dermomyotome undergoes cellular expansion thereby pushing the ventral lateral lip in a lateral direction (translocation). In contrast, the alternative view holds that the ventral lateral lip grows laterally. RESULTS: Using time lapse confocal microscopy, we observed that the GFP-labelled ventrolateral lip (VLL) of the dermomyotome grows rather than translocates in a lateral direction. The necessity of the VLL for lateral extension of the myotome was addressed by ablation studies. We found that the hypaxial myotome did not form after VLL ablation. In contrast, the removal of an intermediate portion of the dermomyotome had very little effect of the hypaxial myotome. These results demonstrate that the VLL is required for the formation of the hypaxial myotome. CONCLUSION: Our study demonstrates that the dermomyotome ventrolateral lip is essential for the hypaxial myotome formation and supports the lip extension model. Therefore, despite being under independent signalling controls, both the dorsomedial and ventrolateral lip fulfil the same function, i.e. they extend into adjacent regions permitting the growth of the myotome.
PMID 24138189 [PubMed - in process] PMCID: PMC3853214
2012
From dynamic expression patterns to boundary formation in the presomitic mesoderm
PLoS Comput Biol. 2012 Jun;8(6):e1002586. Epub 2012 Jun 28.
Tiedemann HB, Schneltzer E, Zeiser S, Hoesel B, Beckers J, Przemeck GK, de Angelis MH. Source Institute of Experimental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
Abstract
The segmentation of the vertebrate body is laid down during early embryogenesis. The formation of signaling gradients, the periodic expression of genes of the Notch-, Fgf- and Wnt-pathways and their interplay in the unsegmented presomitic mesoderm (PSM) precedes the rhythmic budding of nascent somites at its anterior end, which later develops into epithelialized structures, the somites. Although many in silico models describing partial aspects of somitogenesis already exist, simulations of a complete causal chain from gene expression in the growth zone via the interaction of multiple cells to segmentation are rare. Here, we present an enhanced gene regulatory network (GRN) for mice in a simulation program that models the growing PSM by many virtual cells and integrates WNT3A and FGF8 gradient formation, periodic gene expression and Delta/Notch signaling. Assuming Hes7 as core of the somitogenesis clock and LFNG as modulator, we postulate a negative feedback of HES7 on Dll1 leading to an oscillating Dll1 expression as seen in vivo. Furthermore, we are able to simulate the experimentally observed wave of activated NOTCH (NICD) as a result of the interactions in the GRN. We esteem our model as robust for a wide range of parameter values with the Hes7 mRNA and protein decays exerting a strong influence on the core oscillator. Moreover, our model predicts interference between Hes1 and HES7 oscillators when their intrinsic frequencies differ. In conclusion, we have built a comprehensive model of somitogenesis with HES7 as core oscillator that is able to reproduce many experimentally observed data in mice.
PMID 22761566
http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1002586
2011
FGF4 and FGF8 comprise the wavefront activity that controls somitogenesis
Proc Natl Acad Sci U S A. 2011 Mar 8;108(10):4018-23. Epub 2011 Feb 22.
Naiche LA, Holder N, Lewandoski M.
Genetics of Vertebrate Development Section, National Cancer Institute, Frederick, MD 21701. Abstract Somites form along the embryonic axis by sequential segmentation from the presomitic mesoderm (PSM) and differentiate into the segmented vertebral column as well as other unsegmented tissues. Somites are thought to form via the intersection of two activities known as the clock and the wavefront. Previous work has suggested that fibroblast growth factor (FGF) activity may be the wavefront signal, which maintains the PSM in an undifferentiated state. However, it is unclear which (if any) of the FGFs expressed in the PSM comprise this activity, as removal of any one gene is insufficient to disrupt early somitogenesis. Here we show that when both Fgf4 and Fgf8 are deleted in the PSM, expression of most PSM genes is absent, including cycling genes, WNT pathway genes, and markers of undifferentiated PSM. Significantly, markers of nascent somite cell fate expand throughout the PSM, demonstrating the premature differentiation of this entire tissue, a highly unusual phenotype indicative of the loss of wavefront activity. When WNT signaling is restored in mutants, PSM progenitor markers are partially restored but premature differentiation of the PSM still occurs, demonstrating that FGF signaling operates independently of WNT signaling. This study provides genetic evidence that FGFs are the wavefront signal and identifies the specific FGF ligands that encode this activity. Furthermore, these data show that FGF action maintains WNT signaling, and that both signaling pathways are required in parallel to maintain PSM progenitor tissue.
PMID: 21368122
The chick somitogenesis oscillator is arrested before all paraxial mesoderm is segmented into somites http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836991/?tool=pmcentrez&report=abstract
2010
Regulator of g protein signaling 3 modulates wnt5b calcium dynamics and somite patterning
PLoS Genet. 2010 Jul 8;6(7):e1001020.
Freisinger CM, Fisher RA, Slusarski DC. Source Department of Biology, University of Iowa, Iowa City, Iowa, United States of America. Abstract Vertebrate development requires communication among cells of the embryo in order to define the body axis, and the Wnt-signaling network plays a key role in axis formation as well as in a vast array of other cellular processes. One arm of the Wnt-signaling network, the non-canonical Wnt pathway, mediates intracellular calcium release via activation of heterotrimeric G proteins. Regulator of G protein Signaling (RGS) proteins can accelerate inactivation of G proteins by acting as G protein GTPase-activating proteins (GAPs), however, the possible role of RGS proteins in non-canonical Wnt signaling and development is not known. Here, we identify rgs3 as having an overlapping expression pattern with wnt5b in zebrafish and reveal that individual knockdown of either rgs3 or wnt5b gene function produces similar somite patterning defects. Additionally, we describe endogenous calcium release dynamics in developing zebrafish somites and determine that both rgs3 and wnt5b function are required for appropriate frequency and amplitude of calcium release activity. Using rescue of gene knockdown and in vivo calcium imaging assays, we demonstrate that the activity of Rgs3 requires its ability to interact with Galpha subunits and function as a G protein GAP. Thus, Rgs3 function is necessary for appropriate frequency and amplitude of calcium release during somitogenesis and is downstream of Wnt5 activity. These results provide the first evidence for an essential developmental role of RGS proteins in modulating the duration of non-canonical Wnt signaling.
PMID: 20628572 http://www.ncbi.nlm.nih.gov/pubmed/20628572
Somitogenesis clock-wave initiation requires differential decay and multiple binding sites for clock protein
PLoS Comput Biol. 2010 Apr 1;6(4):e1000728.
Campanelli M, Gedeon T. Source Department of Mathematics and Computer Science, Southwest Minnesota State University, Marshall, Minnesota, United States of America. Abstract Somitogenesis is a process common to all vertebrate embryos in which repeated blocks of cells arise from the presomitic mesoderm (PSM) to lay a foundational pattern for trunk and tail development. Somites form in the wake of passing waves of periodic gene expression that originate in the tailbud and sweep posteriorly across the PSM. Previous work has suggested that the waves result from a spatiotemporally graded control protein that affects the oscillation rate of clock-gene expression. With a minimally constructed mathematical model, we study the contribution of two control mechanisms to the initial formation of this gene-expression wave. We test four biologically motivated model scenarios with either one or two clock protein transcription binding sites, and with or without differential decay rates for clock protein monomers and dimers. We examine the sensitivity of wave formation with respect to multiple model parameters and robustness to heterogeneity in cell population. We find that only a model with both multiple binding sites and differential decay rates is able to reproduce experimentally observed waveforms. Our results show that the experimentally observed characteristics of somitogenesis wave initiation constrain the underlying genetic control mechanisms.
PMID: 20369016 http://www.ncbi.nlm.nih.gov/pubmed/20369016
Sonic hedgehog in temporal control of somite formation
Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):12907-12. Epub 2010 Jul 1.
Resende TP, Ferreira M, Teillet MA, Tavares AT, Andrade RP, Palmeirim I. Source Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, 4710-057 Braga, Portugal.
Abstract
Vertebrate embryo somite formation is temporally controlled by the cyclic expression of somitogenesis clock genes in the presomitic mesoderm (PSM). The somitogenesis clock is believed to be an intrinsic property of this tissue, operating independently of embryonic midline structures and the signaling molecules produced therein, namely Sonic hedgehog (Shh). This work revisits the notochord signaling contribution to temporal control of PSM segmentation by assessing the rate and number of somites formed and somitogenesis molecular clock gene expression oscillations upon notochord ablation. The absence of the notochord causes a delay in somite formation, accompanied by an increase in the period of molecular clock oscillations. Shh is the notochord-derived signal responsible for this effect, as these alterations are recapitulated by Shh signaling inhibitors and rescued by an external Shh supply. We have characterized chick smoothened expression pattern and have found that the PSM expresses both patched1 and smoothened Shh signal transducers. Upon notochord ablation, patched1, gli1, and fgf8 are down-regulated, whereas gli2 and gli3 are overexpressed. Strikingly, notochord-deprived PSM segmentation rate recovers over time, concomitant with raldh2 overexpression. Accordingly, exogenous RA supplement rescues notochord ablation effects on somite formation. A model is presented in which Shh and RA pathways converge to inhibit PSM Gli activity, ensuring timely somite formation. Altogether, our data provide evidence that a balance between different pathways ensures the robustness of timely somite formation and that notochord-derived Shh is a component of the molecular network regulating the pace of the somitogenesis clock.
PMID: 20615943 http://www.ncbi.nlm.nih.gov/pubmed/20615943
2009
Sprouty4, an FGF inhibitor, displays cyclic gene expression under the control of the notch segmentation clock in the mouse PSM
PLoS One. 2009;4(5):e5603. Epub 2009 May 19.
Hayashi S, Shimoda T, Nakajima M, Tsukada Y, Sakumura Y, Dale JK, Maroto M, Kohno K, Matsui T, Bessho Y. Source Laboratory of Gene Regulation Research, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Japan.
Abstract BACKGROUND: During vertebrate embryogenesis, somites are generated at regular intervals, the temporal and spatial periodicity of which is governed by a gradient of fibroblast growth factor (FGF) and/or Wnt signaling activity in the presomitic mesoderm (PSM) in conjunction with oscillations of gene expression of components of the Notch, Wnt and FGF signaling pathways.
PRINCIPAL FINDINGS: Here, we show that the expression of Sprouty4, which encodes an FGF inhibitor, oscillates in 2-h cycles in the mouse PSM in synchrony with other oscillating genes from the Notch signaling pathway, such as lunatic fringe. Sprouty4 does not oscillate in Hes7-null mutant mouse embryos, and Hes7 can inhibit FGF-induced transcriptional activity of the Sprouty4 promoter.
CONCLUSIONS: Thus, periodic expression of Sprouty4 is controlled by the Notch segmentation clock and may work as a mediator that links the temporal periodicity of clock gene oscillations with the spatial periodicity of boundary formation which is regulated by the gradient of FGF/Wnt activity.
PMID 19440349
Notch is a critical component of the mouse somitogenesis oscillator and is essential for the formation of the somites
PLoS Genet. 2009 Sep;5(9):e1000662. Epub 2009 Sep 25.
Ferjentsik Z, Hayashi S, Dale JK, Bessho Y, Herreman A, De Strooper B, del Monte G, de la Pompa JL, Maroto M. Source Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom. Abstract Segmentation of the vertebrate body axis is initiated through somitogenesis, whereby epithelial somites bud off in pairs periodically from the rostral end of the unsegmented presomitic mesoderm (PSM). The periodicity of somitogenesis is governed by a molecular oscillator that drives periodic waves of clock gene expression caudo-rostrally through the PSM with a periodicity that matches somite formation. To date the clock genes comprise components of the Notch, Wnt, and FGF pathways. The literature contains controversial reports as to the absolute role(s) of Notch signalling during the process of somite formation. Recent data in the zebrafish have suggested that the only role of Notch signalling is to synchronise clock gene oscillations across the PSM and that somite formation can continue in the absence of Notch activity. However, it is not clear in the mouse if an FGF/Wnt-based oscillator is sufficient to generate segmented structures, such as the somites, in the absence of all Notch activity. We have investigated the requirement for Notch signalling in the mouse somitogenesis clock by analysing embryos carrying a mutation in different components of the Notch pathway, such as Lunatic fringe (Lfng), Hes7, Rbpj, and presenilin1/presenilin2 (Psen1/Psen2), and by pharmacological blocking of the Notch pathway. In contrast to the fish studies, we show that mouse embryos lacking all Notch activity do not show oscillatory activity, as evidenced by the absence of waves of clock gene expression across the PSM, and they do not develop somites. We propose that, at least in the mouse embryo, Notch activity is absolutely essential for the formation of a segmented body axis.
PMID 19779553
2003
Somites, spinal Ganglia, and centra. Enumeration and interrelationships in staged human embryos, and implications for neural tube defects
Cells Tissues Organs. 2003;173(2):75-92.
O'Rahilly R, Müller F. Source School of Medicine, University of California, Davis, USA.
Abstract
Serial sections of 99 human embryos from Carnegie stages 8-23 were investigated and 38 graphic reconstructions were evaluated. At stage 9 somite 1 is of appreciable size and is separated from the otic disc, as also in the next several stages by rhombomeres and pharyngeal arches 3 and 4, thereby differing from the chick. At stage 10 somite 1 begins to differentiate into sclerotome and dermatomyotome. At stage 11 spinal neural crest begins to develop. At stage 12 parts of somites 1-4 are being transformed into the hypoglossal cell cord. It is stressed that the numbers of somites present at stages 9-12 are part of the definition of those stages. At stage 13 dense and loose zones begin to be detectable rostrally in the sclerotomes and also, although out of phase, in the perinotochord. Spinal ganglia begin to develop in phase with the somites. At stages 14-16 the maximum number of somites observed was 38-39 rather than 42-44, as usually given. Moreover, they did not extend to the tapered end of the trunk, which is not a (vertebrated) 'tail'. At stages 17-23 the maximum number of centra was 38-39, including coccygeal vertebrae 4-5. Although most of the somites appear during primary development, all of the spinal ganglia develop during secondary development (stages 13-18). The number of ganglia was at a maximum of 35 at stage 18, but was reduced to 32 already by stage 23. Important points confirmed in this study are that the number of occipital somites in the human is four, and that the level of final closure of the caudal neuropore is future somite 31, which represents approximately future sacral vertebra 2. The interpretation of relevant neural tube defects is discussed in the light of the findings. The ascensus of the conus medullaris during the fetal period is well established, but a concomitant ascent of the situs neuroporicus is proposed here, and has implications for defects that involve tethering of the spinal cord. The main results are integrated in comprehensive graphic representations of the levels and the interrelationships of (a) somites and centra, and (b) somites, neural crest, and spinal ganglia. These may aid in the elucidation of some frequently occurring anomalous conditions.
Copyright 2003 S. Karger AG, Basel
PMID 12649586
