Somitogenesis in Vertebrate Development


A segmented body plan is a conserved feature of all vertebrate species and is established early in embryonic development by the formation of somites, the precursors to the skeleton, musculature and dermis. These epithelialised structures are formed with a species‐specific periodicity during the process of somitogenesis. Gathering evidence suggests that somitogenesis is regulated by a molecular oscillator mechanism that, together with a morphogenic gradient, stipulates when and where somites form. Mutations in key molecular players in this mechanism have been closely linked to developmental disorders and segmental malformations. It is therefore of great medical interest to elucidate the regulatory mechanisms which govern this key developmental process, much of which is still not yet fully understood.

Key Concepts

  • A segmented body plan is a conserved feature of all vertebrate species.
  • Somitogenesis describes the periodic formation of somites, which is the first overt sign of segmentation to appear in the embryonic vertebrate body plan.
  • The temporal periodicity of somitogenesis is thought to be regulated by a molecular oscillator mechanism termed the segmentation clock.
  • There is emerging evidence to suggest a significant degree of conservation of the regulatory mechanisms governing somitogenesis in different vertebrate species.
  • Some particular disease states characterised by segmentation defects have been shown to result from mutation in key Notch‐regulated components of somitogenesis.
  • Many of the mechanisms thought to regulate somitogenesis and somite boundary formation appear to be highly reliant on the Notch signalling pathway.
  • There is a large degree of crosstalk between the Notch, Wnt and FGF signalling pathways that orchestrate somitogenesis.
  • Future advances in our understanding of the regulatory mechanisms governing somitogenesis rely on developing mathematical models and interdisciplinary approaches to direct and cooperate with biological investigation.

Keywords: vertebrate segmentation; molecular oscillations; clock; wavefront; Notch signalling; molecular crosstalk; mathematical modelling; somites

Figure 1. Somite maturation in the vertebrate embryo . In the newly formed somite, an epithelial layer of mesodermal cells surrounds a central lumen termed the somitocoel which contains loose mesenchyme cells. As the somite matures, the ventral epithelial cells disaggregate and together with the somitocoel, become the sclerotome. The remaining epithelial cells differentiate into the dermomyotome. SE, surface ectoderm; DRG, dorsal root ganglion; NC, notochord; FP, floor plate; NT, neural tube.
Figure 2. Phenotypes of spondylocostal dysostosis (SCD) . The formation of hemi‐vertebrae (a) and fused ribs (b) together with shortening of the body axis and vertebral transformations are associated with the SCD phenotype. Mutations in key regulatory components of somitogenesis; Dll3 (Turnpenny et al., ), Mesp2 (Whittock et al., ), Lunatic fringe (Lfng) (Sparrow et al., ) and Hairy and Enhancer of Split 7 (Hes7) (Sparrow et al., ), have been linked to SCD (c) indicating that disruption of somite and boundary formation underlies this phenotype in these patients. Images are sourced from the indicated primary references. Dll3: Reproduced with permission form Turnpenny 2007 © John Wiley and Sons. Mesp2: Reproduced from Whittock 2004 © Elsevier. Lfng: Reproduced from Sparrow et al 2006 © Elsevier. Hes7: Reproduced from Sparrow et al 2010 © Nature Publishing Group.
Figure 3. The characterisation of the vertebrate segmentation clock oscillator . Waves of gene transcription from clock genes appear to originate in the tail‐bud of the pre‐somitic mesoderm (PSM) and progress caudo‐rostrally across this tissue with a periodicity which matches somite formation. The progress of these oscillations across this tissue is described in well‐characterised phases (a). Somite boundary formation occurs between phase 2 and 3 of the segmentation clock cycle. In chick, dissection of the PSM from neighbouring tissues to remove external cues and/or division of the PSM into multiple pieces does not prevent correctly timed coherent oscillations in clock gene expression indicating the cell autonomy of this process. In both chick and zebrafish, dissociation of PSM cells completely from their neighbours does not prevent oscillations but results in a loss of synchrony between cells (b).
Figure 4. The intracellular oscillations of the segmentation clock are governed predominantly by transient negative feedback loops . Trans‐activation of Notch signalling between adjacent cells initiates a series of cleavage events that liberate the intracellular portion of the Notch receptor (NICD). NICD associates with additional cofactors in the nucleus of the signal receiving cell to activate downstream target genes. Lfng acts to inhibit Notch signalling via post‐translational modification of Notch receptor while Hes7 binds as a dimer to the promoter sequences of Notch target genes, including its own promoter and prevents activation of transcription. However, both Lfng and Hes7 are actively and rapidly degraded allowing for the next wave of signalling. Therefore, the auto‐repression of Notch signalling is transient and leads to pulsatile transcription.
Figure 5. Sources of delay in the segmentation clock oscillation period . The total period of segmentation clock cycle is the sum of the time taken for the following identifiable processes: clock gene transcription, intron splicing, mRNA nuclear export, translation, nuclear import, protein complex assembly, DNA binding and protein/mRNA decay.
Figure 6. The wavefront activity of the PSM may control somite size . The wavefront activity of the PSM is thought to be established by opposing gradients of FGF/Wnt and retinoic acid (RA). The intersection of these gradients is termed the determination front and once cells become displaced rostral to that point in the PSM they can respond to the molecular oscillator and embark on their segmentation programme (a). Studies in the chick have shown that the position of the determination front and hence somite size can be altered by manipulation of FGF signalling such as with the FGFR inhibitor SU5402 (b) or an Fgf8 soaked bead (c).
Figure 7. The molecular cascade of somite boundary formation and morphological re‐segmentation of the sclerotome . Expression domains of key components of the segmentation machinery are indicated by colour coded bars in the PSM schematic shown in (a) and (b). Expression of Mesp2 (magenta) is promoted in the rostral PSM (S‐1) by the cooperation of Notch activity (NICD; dark blue) and Tbx6 (green) (1). As the segmentation clock cycle progresses, Mesp2 actively downregulates its own transcription via inhibition of key transcriptional regulators MamL and Tbx6 and activation of the Notch signalling inhibitor Lfng (not shown). The Mesp2 expression domain is further refined by the action of transcriptional repressor Ripply1/2 (purple) (2). Notch activity is thereby restricted to the caudal half of the forming somite, while Mesp2 becomes restricted to the rostral half which establishes the subdivision of the somites. As somites begin to mature and differentiate, the sclerotome from the caudal half of one somite fuses with the rostral half of its neighbour to form the definitive vertebrae, in a process termed re‐segmentation.
Figure 8. Establishing anterior–posterior (AP) polarity of the body axis using the Hox gene code . Vertebrae have distinct morphologies depending on their location along the AP axis. Hox genes provide the basis for this specification. These genes are expressed in restricted domains along the axis. Different combinations of genes, referred to as the Hox code, expressed within different somites specify different vertebra characteristics. The Hox code underlying specification of each vertebra along the antero‐posterior body axis of the mouse is shown here. Reproduced with permission from Dr Robert A. Bone.


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Further Reading

Graham A et al. (2014) What can vertebrates tell us about segmentation? EvoDevo 5 (1): 24.

Hubaud A and Pourquié O (2014) Signalling dynamics in vertebrate segmentation. Nature Reviews. Molecular Cell Biology 15 (11): 709–721.

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Saga Y (2012b) The mechanism of somite formation in mice. Current Opinion in Genetics & Development 22 (4): 331–338.

Wahi K , Bochter MS and Cole SE (2014) The many roles of Notch signaling during vertebrate somitogenesis. Seminars in Cell & Developmental Biology. DOI: 10.1016/j.semcdb.2014.11.010.

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Bailey, Charlotte, and Dale, Kim(Jun 2015) Somitogenesis in Vertebrate Development. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0003820.pub2]