Somitogenesis

Stable Identifier
R-HSA-9824272
DOI
10.3180/R-HSA-9824272.1
Type
Pathway
Species
Homo sapiens
ReviewStatus
5/5
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Somitogenesis
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Somites are bounded segments of mesenchyme that are periodically cleaved, or segmented, from the developing anterior paraxial mesoderm (Diaz-Cuadros et al. 2020). Somite formation is conceptualized using a clock and wavefront model (reviewed in Saga 2012). The clock is present in cells of the presomitic mesoderm and cycles between a permissive state in which segmentation can occur and a refractory state in which it cannot. The wavefront moves along the presomitic mesoderm and causes segmentation where and when it encounters cells in the permissive state, thus the size of the somites is determined by the periodicity of the clock and the migration speed of the wavefront.
The segmentation process is driven by WNY signaling, FGF signaling, and especially the Notch signaling (reviewed in Dunwoodie et al. 2009, Ferjentsik et al. 2009), Hubaud and Pourquie 2014). The intersection of posterior-anterior gradients of WNT and FGF signaling and an anterior-posterior gradient of retinoic acid signaling regulates the position of somite boundaries as perturbation of any of the gradients affects somite boundaries (reviewed in Gibb et al. 2010, Hubard and Pourquie et al. 2014). Thus WNT, FGF, and retinoic acid appear to form the wavefront, also called the determination front. Segmentation periodicity is controlled by HES7-mediated negative feedback loops in the Notch pathway, which constitute a molecular oscillator or segmentation clock (Bessho et al. 2003). Activation of LFNG expression by Notch and inhibition of Notch signaling by LFNG, possibly via regulation of the DLL3 ligand (Bochter et al. 2022), constitute another negative feedback loop that acts as a molecular oscillator (Dale et al. 2003, Falk et al. 2022). Clock oscillations are initiated in nascent presomitic mesoderm in the primitive streak of the gastrulating embryo (Falk et al. 2022) and posterior-to-anterior waves sweep to anterior paraxial mesoderm to regulate MESP2/RIPPLY2 expression to initiate segmentation. MESP2 activates expression of EPHA4 (Nakajima et al. 2006), an Eph receptor that participates in segment boundary formation. MESP2 also activates expression of RIPPLY2 (Morimoto et al. 2007), an inhibitor of TBX6 (Zhao et al. 2018). TBX6 is an activator of MESP2, therefore MESP2 indirectly inhibits its own expression via RIPPLY2.
Mutations in components of the segmentation clock, for example DLL3, MESP2, LFNG, and HES7, cause congenital vertebral defects in humans (Dunwoodie et al. 2009, Nóbrega et al. 2021).
Literature References
PubMed ID Title Journal Year
19779553 Notch is a critical component of the mouse somitogenesis oscillator and is essential for the formation of the somites

Bessho, Y, De Strooper, B, Herreman, A, Maroto, M, De La Pompa, JL, Ferjentsik, Z, Del Monte, G, Dale, JK, Hayashi, S

PLoS Genet 2009
31915384 In vitro characterization of the human segmentation clock

Hubaud, A, Al Tanoury, Z, Miyawaki, A, Budjan, C, Diaz-Cuadros, M, Pourquié, O, Yoshioka-Kobayashi, K, Tarazona, OA, Wagner, DE, Michaut, A, Niino, Y, Kageyama, R, Donelly, S, Touboul, J

Nature 2020
20724159 The segmentation clock mechanism moves up a notch

Gibb, S, Maroto, M, Dale, JK

Trends Cell Biol 2010
16728472 Identification of Epha4 enhancer required for segmental expression and the regulation by Mesp2

Saga, Y, Koseki, H, Nakajima, Y, Morimoto, M, Takahashi, Y

Development 2006
19608404 The role of Notch in patterning the human vertebral column

Dunwoodie, SL

Curr Opin Genet Dev 2009
12783854 Periodic repression by the bHLH factor Hes7 is an essential mechanism for the somite segmentation clock

Hirata, H, Bessho, Y, Masamizu, Y, Kageyama, R

Genes Dev 2003
22742849 The mechanism of somite formation in mice

Saga, Y

Curr Opin Genet Dev 2012
12529645 Periodic notch inhibition by lunatic fringe underlies the chick segmentation clock

Pourquie, O, Dale, JK, Malapert, P, Maroto, M, McGrew, M, Dequeant, ML

Nature 2003
29761784 Ripply2 recruits proteasome complex for Tbx6 degradation to define segment border during murine somitogenesis

Saga, Y, Oginuma, M, Okubo, A, Ajima, R, Kiso, M, Zhao, W

Elife 2018
33572886 Altered Cogs of the Clock: Insights into the Embryonic Etiology of Spondylocostal Dysostosis

Maia-Fernandes, AC, Nóbrega, A, Andrade, RP

J Dev Biol 2021
35686648 Imaging the onset of oscillatory signaling dynamics during mouse embryo gastrulation

Falk, HJ, McDole, K, Mönke, G, Tomita, T, Aulehla, A

Development 2022
25335437 Signalling dynamics in vertebrate segmentation

Pourquié, O, Hubaud, A

Nat Rev Mol Cell Biol 2014
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somitogenesis (0001756)
Authored
Chalamalasetty, RB  (2022-11-09)
Yamaguchi, TP  (2022-11-09)
May, B  (2023-01-14)
Reviewed
Yamaguchi, TP  (2023-05-09)
Chalamalasetty, RB  (2023-05-09)
Created
May, B  (2023-01-18)
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