Abstract
Segmentation is a fundamental feature of the vertebrate body plan. This metameric organization is first implemented by somitogenesis in the early embryo, when paired epithelial blocks called somites are rhythmically formed to flank the neural tube. Recent advances in in vitro models have offered new opportunities to elucidate the mechanisms that underlie somitogenesis. Notably, models derived from human pluripotent stem cells introduced an efficient proxy for studying this process during human development. In this Review, we summarize the current understanding of somitogenesis gained from both in vivo studies and in vitro studies. We deconstruct the spatiotemporal dynamics of somitogenesis into four distinct modules: dynamic events in the presomitic mesoderm, segmental determination, somite anteroposterior polarity patterning, and epithelial morphogenesis. We first focus on the segmentation clock, as well as signalling and metabolic gradients along the tissue, before discussing the clock and wavefront and other models that account for segmental determination. We then detail the molecular and cellular mechanisms of anteroposterior polarity patterning and somite epithelialization.
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References
Hubaud, A. & Pourquié, O. Signalling dynamics in vertebrate segmentation. Nat. Rev. Mol. Cell Biol. 15, 709–721 (2014).
Bulman, M. P. et al. Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nat. Genet. 24, 438–441 (2000).
Sparrow, D. B., Guillén-Navarro, E., Fatkin, D. & Dunwoodie, S. L. Mutation of Hairy-and-Enhancer-of-Split-7 in humans causes spondylocostal dysostosis. Hum. Mol. Genet. 17, 3761–3766 (2008).
Whittock, N. V. et al. Mutated MESP2 causes spondylocostal dysostosis in humans. Am. J. Hum. Genet. 74, 1249–1254 (2004).
McInerney-Leo, A. M. et al. Compound heterozygous mutations in RIPPLY2 associated with vertebral segmentation defects. Hum. Mol. Genet. 24, 1234–1242 (2015).
Cornier, A. S. et al. Mutations in the MESP2 gene cause spondylothoracic dysostosis/Jarcho–Levin syndrome. Am. J. Hum. Genet. 82, 1334–1341 (2008).
Sparrow, D. B. et al. A mechanism for gene-environment interaction in the etiology of congenital scoliosis. Cell 149, 295–306 (2012).
Bouman, A. et al. Homozygous DMRT2 variant associates with severe rib malformations in a newborn. Am. J. Med. Genet. A 176, 1216–1221 (2018).
Turnpenny, P. D. et al. Novel mutations in DLL3, a somitogenesis gene encoding a ligand for the Notch signalling pathway, cause a consistent pattern of abnormal vertebral segmentation in spondylocostal dysostosis. J. Med. Genet. 40, 333–339 (2003).
Sparrow, D. B. et al. Autosomal dominant spondylocostal dysostosis is caused by mutation in TBX6. Hum. Mol. Genet. 22, 1625–1631 (2013).
Mohamed, J. Y. et al. Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel–Feil anomaly. Am. J. Hum. Genet. 92, 157–161 (2013).
Bayrakli, F. et al. Mutation in MEOX1 gene causes a recessive Klippel–Feil syndrome subtype. BMC Genet. 14, 95 (2013).
Sparrow, D. B. et al. Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype. Am. J. Hum. Genet. 78, 28–37 (2006).
Gomez, C. et al. Control of segment number in vertebrate embryos. Nature 454, 335–339 (2008).
Gomez, C. & Pourquié, O. Developmental control of segment numbers in vertebrates. J. Exp. Zool. B Mol. Dev. Evol. 312, 533–544 (2009).
Kuan, C.-Y. K., Tannahill, D., Cook, G. M. W. & Keynes, R. J. Somite polarity and segmental patterning of the peripheral nervous system. Mech. Dev. 121, 1055–1068 (2004).
Fleming, A., Kishida, M. G., Kimmel, C. B. & Keynes, R. J. Building the backbone: the development and evolution of vertebral patterning. Development 142, 1733–1744 (2015).
Scaal, M. Early development of the vertebral column. Semin. Cell Dev. Biol. 49, 83–91 (2016).
Oates, A. C., Morelli, L. G. & Ares, S. Patterning embryos with oscillations: structure, function and dynamics of the vertebrate segmentation clock. Development 139, 625–639 (2012).
Diaz-Cuadros, M. & Pourquie, O. In vitro systems: a new window to the segmentation clock. Dev. Growth Differ. 63, 140–153 (2021).
Lauschke, V. M., Tsiairis, C. D., François, P. & Aulehla, A. Scaling of embryonic patterning based on phase-gradient encoding. Nature 493, 101–105 (2013).
Hubaud, A., Regev, I., Mahadevan, L. & Pourquié, O. Excitable dynamics and yap-dependent mechanical cues drive the segmentation clock. Cell 171, 668–682.e11 (2017).
Simsek, M. F. & Özbudak, E. M. Spatial fold change of FGF signaling encodes positional information for segmental determination in zebrafish. Cell Rep. 24, 66–78.e8 (2018).
Matsumiya, M., Tomita, T., Yoshioka-Kobayashi, K., Isomura, A. & Kageyama, R. ES cell-derived presomitic mesoderm-like tissues for analysis of synchronized oscillations in the segmentation clock. Development 145, dev156836 (2018).
Chu, L.-F. et al. An in vitro human segmentation clock model derived from embryonic stem cells. Cell Rep. 28, 2247–2255.e5 (2019).
Matsuda, M. et al. Recapitulating the human segmentation clock with pluripotent stem cells. Nature 580, 124–129 (2020).
Diaz-Cuadros, M. et al. In vitro characterization of the human segmentation clock. Nature 580, 113–118 (2020). Together with references 25 and 26, this article establishes in vitro systems using human PSCs to identify the human segmentation clock.
van den Brink, S. C. et al. Single-cell and spatial transcriptomics reveal somitogenesis in gastruloids. Nature 582, 405–409 (2020).
Veenvliet, J. V. et al. Mouse embryonic stem cells self-organize into trunk-like structures with neural tube and somites. Science 370, eaba4937 (2020).
Sanaki-Matsumiya, M. et al. Periodic formation of epithelial somites from human pluripotent stem cells. Nat. Commun. 13, 2325 (2022).
Miao, Y. et al. Reconstruction and deconstruction of human somitogenesis in vitro. Nature 614, 500–508 (2023). This article establishes two organoid models of human somite formation, called somitoid and segmentoid, and reveals that cell sorting underlies somite anteroposterior polarity patterning.
Yamanaka, Y. et al. Reconstituting human somitogenesis in vitro. Nature 614, 509–520 (2023). Here, the authors establish an organoid model of human somite formation called axioloid, characterize the model in detail and identify a crucial role of retinoic acid in somite epithelization in vitro.
Yaman, Y. I. & Ramanathan, S. Controlling human organoid symmetry breaking reveals signaling gradients drive segmentation clock waves. Cell 186, 497–512 (2023). This article reports the use of bioengineering tools to establish an organoid model of human trunk consisting of the neural tube and somites and delineates roles of signalling gradients in regulating the wave dynamics of clock oscillations.
Schoenwolf, G. C., Bleyl, S. B., Brauer, P. R. & Francis-West, P. H. Larsen’s Human Embryology E-Book (Elsevier Health Sciences, 2020).
Palmeirim, I., Henrique, D., Ish-Horowicz, D. & Pourquié, O. Avian hairy gene expression identifies a molecular clock linked to vertebrate segmentation and somitogenesis. Cell 91, 639–648 (1997).
Masamizu, Y. et al. Real-time imaging of the somite segmentation clock: revelation of unstable oscillators in the individual presomitic mesoderm cells. Proc. Natl Acad. Sci. USA 103, 1313–1318 (2006).
Aulehla, A. et al. A β-catenin gradient links the clock and wavefront systems in mouse embryo segmentation. Nat. Cell Biol. 10, 186 (2007).
Webb, A. B. et al. Persistence, period and precision of autonomous cellular oscillators from the zebrafish segmentation clock. eLife 5, e08438 (2016).
Tsiairis, C. D. & Aulehla, A. Self-organization of embryonic genetic oscillators into spatiotemporal wave patterns. Cell 164, 656–667 (2016).
Sonnen, K. F. et al. Modulation of phase shift between wnt and Notch signaling oscillations controls mesoderm segmentation. Cell 172, 1079–1090.e12 (2018). The authors develop a microfluidic device to entrain oscillations of WNT and Notch signalling and propose that the phase relationship between clock sub-oscillators encodes positional information for segmental determination.
Chal, J. et al. Differentiation of pluripotent stem cells to muscle fiber to model Duchenne muscular dystrophy. Nat. Biotechnol. 33, 962–969 (2015).
Iimura, T., Yang, X., Weijer, C. J. & Pourquié, O. Dual mode of paraxial mesoderm formation during chick gastrulation. Proc. Natl Acad. Sci. USA 104, 2744–2749 (2007).
Tzouanacou, E., Wegener, A., Wymeersch, F. J., Wilson, V. & Nicolas, J.-F. Redefining the progression of lineage segregations during mammalian embryogenesis by clonal analysis. Dev. Cell 17, 365–376 (2009).
Gouti, M. et al. A gene regulatory network balances neural and mesoderm specification during vertebrate trunk development. Dev. Cell 41, 243–261.e7 (2017).
Attardi, A. et al. Neuromesodermal progenitors are a conserved source of spinal cord with divergent growth dynamics. Development 145, dev166728 (2018).
Guillot, C., Djeffal, Y., Michaut, A., Rabe, B. & Pourquié, O. Dynamics of primitive streak regression controls the fate of neuromesodermal progenitors in the chicken embryo. eLife 10, e64819 (2021).
Aulehla, A. et al. Wnt3a plays a major role in the segmentation clock controlling somitogenesis. Dev. Cell 4, 395–406 (2003).
Chapman, S. C., Brown, R., Lees, L., Schoenwolf, G. C. & Lumsden, A. Expression analysis of chick Wnt and frizzled genes and selected inhibitors in early chick patterning. Dev. Dyn. 229, 668–676 (2004).
Dubrulle, J. & Pourquié, O. fgf8 mRNA decay establishes a gradient that couples axial elongation to patterning in the vertebrate embryo. Nature 427, 419–422 (2004).
Streit, A. & Stern, C. D. Establishment and maintenance of the border of the neural plate in the chick: involvement of FGF and BMP activity. Mech. Dev. 82, 51–66 (1999).
Robertson, E. J. Dose-dependent Nodal/Smad signals pattern the early mouse embryo. Semin. Cell Dev. Biol. 32, 73–79 (2014).
Zinski, J., Tajer, B. & Mullins, M. C. TGF-β family signaling in early vertebrate development. Cold Spring Harb. Perspect. Biol. 10, a033274 (2018).
Loh, K. M. et al. Mapping the pairwise choices leading from pluripotency to human bone, heart, and other mesoderm cell types. Cell 166, 451–467 (2016).
Nakajima, T. et al. Modeling human somite development and fibrodysplasia ossificans progressiva with induced pluripotent stem cells. Development 145, dev165431 (2018).
Xi, H. et al. In vivo human somitogenesis guides somite development from hPSCs. Cell Rep. 18, 1573–1585 (2017).
Beccari, L. et al. Multi-axial self-organization properties of mouse embryonic stem cells into gastruloids. Nature 562, 272–276 (2018).
Moris, N. et al. An in vitro model of early anteroposterior organization during human development. Nature 582, 410–415 (2020).
Budjan, C. et al. Paraxial mesoderm organoids model development of human somites. eLife 11, e68925 (2022).
Gribaudo, S. et al. Self-organizing models of human trunk organogenesis recapitulate spinal cord and spine co-morphogenesis. Nat. Biotechnol. https://doi.org/10.1038/s41587-023-01956-9 (2023).
Anand, G. M. et al. Controlling organoid symmetry breaking uncovers an excitable system underlying human axial elongation. Cell 186, 497–512.e23 (2023).
Karzbrun, E. et al. Human neural tube morphogenesis in vitro by geometric constraints. Nature 599, 268–272 (2021).
Gjorevski, N. et al. Tissue geometry drives deterministic organoid patterning. Science 375, eaaw9021 (2022).
Soroldoni, D. et al. Genetic oscillations. A doppler effect in embryonic pattern formation. Science 345, 222–225 (2014).
Delaune, E. A., François, P., Shih, N. P. & Amacher, S. L. Single-cell-resolution imaging of the impact of Notch signaling and mitosis on segmentation clock dynamics. Dev. Cell 23, 995–1005 (2012).
Pourquié, O. A brief history of the segmentation clock. Dev. Biol. 485, 24–36 (2022).
Matsuda, M. et al. Species-specific segmentation clock periods are due to differential biochemical reaction speeds. Science 369, 1450–1455 (2020).
Diaz-Cuadros, M. et al. Metabolic regulation of species-specific developmental rates. Nature 613, 550–557 (2023).
Lázaro, J. et al. A stem cell zoo uncovers intracellular scaling of developmental tempo across mammals. Cell Stem Cell 30, 907–908 (2023).
Krol, A. J. et al. Evolutionary plasticity of segmentation clock networks. Development 138, 2783–2792 (2011).
Prince, V. E. et al. Zebrafish lunatic fringe demarcates segmental boundaries. Mech. Dev. 105, 175–180 (2001).
McGrew, M. J., Dale, J. K., Fraboulet, S. & Pourquié, O. The lunatic fringe gene is a target of the molecular clock linked to somite segmentation in avian embryos. Curr. Biol. 8, 979–982 (1998).
Forsberg, H., Crozet, F. & Brown, N. A. Waves of mouse lunatic fringe expression, in four-hour cycles at two-hour intervals, precede somite boundary formation. Curr. Biol. 8, 1027–1030 (1998).
Aulehla, A. & Johnson, R. L. Dynamic expression of lunatic fringe suggests a link between Notch signaling and an autonomous cellular oscillator driving somite segmentation. Dev. Biol. 207, 49–61 (1999).
Dale, J. K. et al. Periodic Notch inhibition by lunatic fringe underlies the chick segmentation clock. Nature 421, 275–278 (2003).
Evrard, Y. A., Lun, Y., Aulehla, A., Gan, L. & Johnson, R. L. Lunatic fringe is an essential mediator of somite segmentation and patterning. Nature 394, 377–381 (1998).
Morales, A. V., Yasuda, Y. & Ish-Horowicz, D. Periodic lunatic fringe expression is controlled during segmentation by a cyclic transcriptional enhancer responsive to Notch signaling. Dev. Cell 3, 63–74 (2002).
Sanchez, P. G. L. et al. Arnold tongue entrainment reveals dynamical principles of the embryonic segmentation clock. eLife 11, e79575 (2022).
Maroto, M., Dale, J. K., Dequéant, M.-L., Petit, A.-C. & Pourquié, O. Synchronised cycling gene oscillations in presomitic mesoderm cells require cell-cell contact. Int. J. Dev. Biol. 49, 309–315 (2005).
Lewis, J. Autoinhibition with transcriptional delay. Curr. Biol. 13, 1398–1408 (2003).
Hirata, H. et al. Oscillatory expression of the bHLH factor Hes1 regulated by a negative feedback loop. Science 298, 840–843 (2002).
Bessho, Y., Hirata, H., Masamizu, Y. & Kageyama, R. Periodic repression by the bHLH factor Hes7 is an essential mechanism for the somite segmentation clock. Genes Dev. 17, 1451–1456 (2003).
Harima, Y., Takashima, Y., Ueda, Y., Ohtsuka, T. & Kageyama, R. Accelerating the tempo of the segmentation clock by reducing the number of introns in the Hes7 gene. Cell Rep. 3, 1–7 (2013).
Hirata, H. et al. Instability of Hes7 protein is crucial for the somite segmentation clock. Nat. Genet. 36, 750–754 (2004).
Takashima, Y., Ohtsuka, T., González, A., Miyachi, H. & Kageyama, R. Intronic delay is essential for oscillatory expression in the segmentation clock. Proc. Natl Acad. Sci. USA 108, 3300–3305 (2011).
Ay, A., Knierer, S., Sperlea, A., Holland, J. & Özbudak, E. M. Short-lived Her proteins drive robust synchronized oscillations in the zebrafish segmentation clock. Development 140, 3244–3253 (2013).
Schröter, C. et al. Topology and dynamics of the zebrafish segmentation clock core circuit. PLoS Biol. 10, e1001364 (2012).
Dale, J. K. et al. Oscillations of the snail genes in the presomitic mesoderm coordinate segmental patterning and morphogenesis in vertebrate somitogenesis. Dev. Cell 10, 355–366 (2006).
Zinani, O. Q. H., Keseroğlu, K., Ay, A. & Özbudak, E. M. Pairing of segmentation clock genes drives robust pattern formation. Nature 589, 431–436 (2020).
Venzin, O. F. & Oates, A. C. What are you synching about? Emerging complexity of Notch signaling in the segmentation clock. Dev. Biol. 460, 40–54 (2020).
Yoshioka-Kobayashi, K. et al. Coupling delay controls synchronized oscillation in the segmentation clock. Nature 580, 119–123 (2020). This article establishes a live imaging system of clock oscillations with single-cell resolution in the mouse embryo and identifies a coupling delay control mechanism by Lfng in maintaining synchronized clock oscillations.
Jiang, Y. J. et al. Notch signalling and the synchronization of the somite segmentation clock. Nature 408, 475–479 (2000).
Horikawa, K., Ishimatsu, K., Yoshimoto, E., Kondo, S. & Takeda, H. Noise-resistant and synchronized oscillation of the segmentation clock. Nature 441, 719–723 (2006).
Mara, A., Schroeder, J., Chalouni, C. & Holley, S. A. Priming, initiation and synchronization of the segmentation clock by deltaD and deltaC. Nat. Cell Biol. 9, 523–530 (2007).
Herrgen, L. et al. Intercellular coupling regulates the period of the segmentation clock. Curr. Biol. 20, 1244–1253 (2010).
Okubo, Y. et al. Lfng regulates the synchronized oscillation of the mouse segmentation clock via trans-repression of Notch signalling. Nat. Commun. 3, 1141 (2012).
Bone, R. A. et al. Spatiotemporal oscillations of Notch1, Dll1 and NICD are coordinated across the mouse PSM. Development 141, 4806–4816 (2014).
Shimojo, H. et al. Oscillatory control of delta-like1 in cell interactions regulates dynamic gene expression and tissue morphogenesis. Genes Dev. 30, 102–116 (2016).
Geffers, I. et al. Divergent functions and distinct localization of the Notch ligands DLL1 and DLL3 vivo. J. Cell Biol. 178, 465–476 (2007).
Ladi, E. et al. The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands. J. Cell Biol. 170, 983–992 (2005).
Wright, G. J. et al. DeltaC and DeltaD interact as Notch ligands in the zebrafish segmentation clock. Development 138, 2947–2956 (2011).
Oates, A. C. Waiting on the fringe: cell autonomy and signaling delays in segmentation clocks. Curr. Opin. Genet. Dev. 63, 61–70 (2020).
Liao, B.-K., Jörg, D. J. & Oates, A. C. Faster embryonic segmentation through elevated delta–Notch signalling. Nat. Commun. 7, 11861 (2016).
Morelli, L. G. et al. Delayed coupling theory of vertebrate segmentation. HFSP J. 3, 55–66 (2009).
Kim, W. et al. The period of the somite segmentation clock is sensitive to Notch activity. Mol. Biol. Cell 22, 3541–3549 (2011).
Wiedermann, G. et al. A balance of positive and negative regulators determines the pace of the segmentation clock. eLife 4, e05842 (2015).
Carrieri, F. A. et al. CDK1 and CDK2 regulate NICD1 turnover and the periodicity of the segmentation clock. EMBO Rep. 20, e46436 (2019).
Takagi, A., Isomura, A., Yoshioka-Kobayashi, K. & Kageyama, R. Dynamic delta-like1 expression in presomitic mesoderm cells during somite segmentation. Gene Expr. Patterns 35, 119094 (2020).
Ay, A. et al. Spatial gradients of protein-level time delays set the pace of the traveling segmentation clock waves. Development 141, 4158–4167 (2014).
Ishimatsu, K., Takamatsu, A. & Takeda, H. Emergence of traveling waves in the zebrafish segmentation clock. Development 137, 1595–1599 (2010).
Gibb, S. et al. Interfering with Wnt signalling alters the periodicity of the segmentation clock. Dev. Biol. 330, 21–31 (2009).
Keskin, S. et al. Noise in the vertebrate segmentation clock is boosted by time delays but tamed by Notch signaling. Cell Rep. 23, 2175–2185.e4 (2018).
Ferjentsik, Z. et al. Notch is a critical component of the mouse somitogenesis oscillator and is essential for the formation of the somites. PLoS Genet. 5, e1000662 (2009).
Falk, H. J., Tomita, T., Mönke, G., McDole, K. & Aulehla, A. Imaging the onset of oscillatory signaling dynamics during mouse embryo gastrulation. Development 149, dev200083 (2022).
Riedel-Kruse, I. H., Müller, C. & Oates, A. C. Synchrony dynamics during initiation, failure, and rescue of the segmentation clock. Science 317, 1911–1915 (2007).
Aulehla, A. & Pourquié, O. Signaling gradients during paraxial mesoderm development. Cold Spring Harb. Perspect. Biol. 2, a000869 (2010).
Niederreither, K., McCaffery, P., Dräger, U. C., Chambon, P. & Dollé, P. Restricted expression and retinoic acid-induced downregulation of the retinaldehyde dehydrogenase type 2 (RALDH-2) gene during mouse development. Mech. Dev. 62, 67–78 (1997).
Sakai, Y. et al. The retinoic acid-inactivating enzyme CYP26 is essential for establishing an uneven distribution of retinoic acid along the anterio-posterior axis within the mouse embryo. Genes Dev. 15, 213–225 (2001).
Oginuma, M. et al. Intracellular pH controls WNT downstream of glycolysis in amniote embryos. Nature 584, 98–101 (2020). This paper identifies that glycolysis regulates WNT signalling in the tailbud by modulating intracellular pH and describes cascades of regulation that links gradients of FGF, glycolysis and WNT signalling along the PSM.
Bulusu, V. et al. Spatiotemporal analysis of a glycolytic activity gradient linked to mouse embryo mesoderm development. Dev. Cell 40, 331–341.e4 (2017).
Oginuma, M. et al. A gradient of glycolytic activity coordinates FGF and Wnt signaling during elongation of the body axis in amniote embryos. Dev. Cell 40, 342–353.e10 (2017).
Miyazawa, H. et al. Glycolytic flux-signaling controls mouse embryo mesoderm development. eLife 11, e83299 (2022).
Niwa, Y. et al. The initiation and propagation of Hes7 oscillation are cooperatively regulated by Fgf and Notch signaling in the somite segmentation clock. Dev. Cell 13, 298–304 (2007).
Kawamura, A. et al. Zebrafish hairy/enhancer of split protein links FGF signaling to cyclic gene expression in the periodic segmentation of somites. Genes Dev. 19, 1156–1161 (2005).
Gibb, S., Maroto, M. & Dale, J. K. The segmentation clock mechanism moves up a Notch. Trends Cell Biol. 20, 593–600 (2010).
Wahl, M. B., Deng, C., Lewandoski, M. & Pourquié, O. FGF signaling acts upstream of the NOTCH and WNT signaling pathways to control segmentation clock oscillations in mouse somitogenesis. Development 134, 4033–4041 (2007).
Anderson, M. J., Magidson, V., Kageyama, R. & Lewandoski, M. Fgf4 maintains Hes7 levels critical for normal somite segmentation clock function. eLife 9, e55608 (2020).
Dequéant, M.-L. et al. A complex oscillating network of signaling genes underlies the mouse segmentation clock. Science 314, 1595–1598 (2006).
Niwa, Y. et al. Different types of oscillations in Notch and Fgf signaling regulate the spatiotemporal periodicity of somitogenesis. Genes Dev. 25, 1115–1120 (2011).
Simsek, M. F. et al. Periodic inhibition of Erk activity drives sequential somite segmentation. Nature 613, 153–159 (2022). This article demonstrates the oscillatory dynamics of phosphorylated Erk gradient in zebrafish, shows that periodic FGF inhibition is sufficient to bring about sequential segmentation without the segmentation clock and proposes a segmentation model whereby the oscillatory clock serves as an upstream input to the wavefront.
Stulberg, M. J., Lin, A., Zhao, H. & Holley, S. A. Crosstalk between Fgf and Wnt signaling in the zebrafish tailbud. Dev. Biol. 369, 298–307 (2012).
Cooke, J. & Zeeman, E. C. A clock and wavefront model for control of the number of repeated structures during animal morphogenesis. J. Theor. Biol. 58, 455–476 (1976).
Dubrulle, J., McGrew, M. J. & Pourquié, O. FGF signaling controls somite boundary position and regulates segmentation clock control of spatiotemporal hox gene activation. Cell 106, 219–232 (2001).
Sawada, A. et al. Fgf/MAPK signalling is a crucial positional cue in somite boundary formation. Development 128, 4873–4880 (2001).
Dunty, W. C. Jr et al. Wnt3a/beta-catenin signaling controls posterior body development by coordinating mesoderm formation and segmentation. Development 135, 85–94 (2008).
Naiche, L. A., Holder, N. & Lewandoski, M. FGF4 and FGF8 comprise the wavefront activity that controls somitogenesis. Proc. Natl Acad. Sci. USA 108, 4018–4023 (2011).
Bajard, L. et al. Wnt-regulated dynamics of positional information in zebrafish somitogenesis. Development 141, 1381–1391 (2014).
Akiyama, R., Masuda, M., Tsuge, S., Bessho, Y. & Matsui, T. An anterior limit of FGF/Erk signal activity marks the earliest future somite boundary in zebrafish. Development 141, 1104–1109 (2014).
Sawada, A. et al. Zebrafish Mesp family genes, mesp-a and mesp-b are segmentally expressed in the presomitic mesoderm, and Mesp-b confers the anterior identity to the developing somites. Development 127, 1691–1702 (2000).
Saga, Y., Hata, N., Koseki, H. & Taketo, M. M. Mesp2: a novel mouse gene expressed in the presegmented mesoderm and essential for segmentation initiation. Genes Dev. 11, 1827–1839 (1997).
Saga, Y. The mechanism of somite formation in mice. Curr. Opin. Genet. Dev. 22, 331–338 (2012).
Yasuhiko, Y. et al. Tbx6-mediated Notch signaling controls somite-specific Mesp2 expression. Proc. Natl Acad. Sci. USA 103, 3651–3656 (2006).
Oginuma, M., Niwa, Y., Chapman, D. L. & Saga, Y. Mesp2 and Tbx6 cooperatively create periodic patterns coupled with the clock machinery during mouse somitogenesis. Development 135, 2555–2562 (2008).
Takahashi, Y. et al. Mesp2 initiates somite segmentation through the Notch signalling pathway. Nat. Genet. 25, 390–396 (2000).
Morimoto, M., Takahashi, Y., Endo, M. & Saga, Y. The Mesp2 transcription factor establishes segmental borders by suppressing Notch activity. Nature 435, 354–359 (2005).
Morimoto, M. et al. The negative regulation of Mesp2 by mouse Ripply2 is required to establish the rostro-caudal patterning within a somite. Development 134, 1561–1569 (2007).
Takahashi, J. et al. Analysis of Ripply1/2-deficient mouse embryos reveals a mechanism underlying the rostro-caudal patterning within a somite. Dev. Biol. 342, 134–145 (2010).
Zhao, W., Ajima, R., Ninomiya, Y. & Saga, Y. Segmental border is defined by Ripply2-mediated Tbx6 repression independent of Mesp2. Dev. Biol. 400, 105–117 (2015).
Moreno, T. A., Jappelli, R., Izpisúa Belmonte, J. C. & Kintner, C. Retinoic acid regulation of the Mesp–Ripply feedback loop during vertebrate segmental patterning. Dev. Biol. 315, 317–330 (2008).
Wanglar, C., Takahashi, J., Yabe, T. & Takada, S. Tbx protein level critical for clock-mediated somite positioning is regulated through interaction between Tbx and Ripply. PLoS ONE 9, e107928 (2014).
Yabe, T., Hoshijima, K., Yamamoto, T. & Takada, S. Quadruple zebrafish mutant reveals different roles of Mesp genes in somite segmentation between mouse and zebrafish. Development 143, 2842–2852 (2016).
Kinoshita, H. et al. Functional roles of the Ripply-mediated suppression of segmentation gene expression at the anterior presomitic mesoderm in zebrafish. Mech. Dev. 152, 21–31 (2018).
Ban, H. et al. Transcriptional autoregulation of zebrafish tbx6 is required for somite segmentation. Development 146, dev177063 (2019).
Yabe, T., Uriu, K. & Takada, S. Ripply suppresses Tbx6 to induce dynamic-to-static conversion in somite segmentation. Nat. Commun. 14, 2115 (2023).
Roy, M. N., Prince, V. E. & Ho, R. K. Heat shock produces periodic somitic disturbances in the zebrafish embryo. Mech. Dev. 85, 27–34 (1999).
Elsdale, T., Pearson, M. & Whitehead, M. Abnormalities in somite segmentation following heat shock to Xenopus embryos. Development 35, 625–635 (1976).
Primmett, D. R., Norris, W. E., Carlson, G. J., Keynes, R. J. & Stern, C. D. Periodic segmental anomalies induced by heat shock in the chick embryo are associated with the cell cycle. Development 105, 119–130 (1989).
Goldbeter, A., Gonze, D. & Pourquié, O. Sharp developmental thresholds defined through bistability by antagonistic gradients of retinoic acid and FGF signaling. Dev. Dyn. 236, 1495–1508 (2007).
Boareto, M., Tomka, T. & Iber, D. Positional information encoded in the dynamic differences between neighboring oscillators during vertebrate segmentation. Cell Dev. 168, 203737 (2021).
Shih, N. P., François, P., Delaune, E. A. & Amacher, S. L. Dynamics of the slowing segmentation clock reveal alternating two-segment periodicity. Development 142, 1785–1793 (2015).
Cotterell, J., Robert-Moreno, A. & Sharpe, J. A local, self-organizing reaction–diffusion model can explain somite patterning in embryos. Cell Syst. 1, 257–269 (2015).
Aoyama, H. & Asamoto, K. The developmental fate of the rostral/caudal half of a somite for vertebra and rib formation: experimental confirmation of the resegmentation theory using chick–quail chimeras. Mech. Dev. 99, 71–82 (2000).
Keynes, R. J. & Stern, C. D. Segmentation in the vertebrate nervous system. Nature 310, 786–789 (1984).
Aoyama, H. & Asamoto, K. Determination of somite cells: independence of cell differentiation and morphogenesis. Development 104, 15–28 (1988).
Nakajima, Y., Morimoto, M., Takahashi, Y., Koseki, H. & Saga, Y. Identification of Epha4 enhancer required for segmental expression and the regulation by Mesp2. Development 133, 2517–2525 (2006).
Koizumi, K. et al. The role of presenilin 1 during somite segmentation. Development 128, 1391–1402 (2001).
Oginuma, M. et al. The oscillation of Notch activation, but not its boundary, is required for somite border formation and rostral–caudal patterning within a somite. Development 137, 1515–1522 (2010).
Sasaki, N., Kiso, M., Kitagawa, M. & Saga, Y. The repression of Notch signaling occurs via the destabilization of mastermind-like 1 by Mesp2 and is essential for somitogenesis. Development 138, 55–64 (2011).
Bussen, M. et al. The T-box transcription factor Tbx18 maintains the separation of anterior and posterior somite compartments. Genes Dev. 18, 1209–1221 (2004).
Hughes, D. S. T., Keynes, R. J. & Tannahill, D. Extensive molecular differences between anterior- and posterior-half-sclerotomes underlie somite polarity and spinal nerve segmentation. BMC Dev. Biol. 9, 30 (2009).
Schrägle, J., Huang, R., Christ, B. & Pröls, F. Control of the temporal and spatial Uncx4.1 expression in the paraxial mesoderm of avian embryos. Anat. Embryol. 208, 323–332 (2004).
Farin, H. F., Mansouri, A., Petry, M. & Kispert, A. T-box protein Tbx18 interacts with the paired box protein Pax3 in the development of the paraxial mesoderm. J. Biol. Chem. 283, 25372–25380 (2008).
Feller, J., Schneider, A., Schuster-Gossler, K. & Gossler, A. Noncyclic Notch activity in the presomitic mesoderm demonstrates uncoupling of somite compartmentalization and boundary formation. Genes Dev. 22, 2166–2171 (2008).
Burgess, R., Rawls, A., Brown, D., Bradley, A. & Olson, E. N. Requirement of the paraxis gene for somite formation and musculoskeletal patterning. Nature 384, 570–573 (1996).
Nomura-Kitabayashi, A. et al. Hypomorphic Mesp allele distinguishes establishment of rostrocaudal polarity and segment border formation in somitogenesis. Development 129, 2473–2481 (2002).
Dias, A. S., de Almeida, I., Belmonte, J. M., Glazier, J. A. & Stern, C. D. Somites without a clock. Science 343, 791–795 (2014).
Horikawa, K., Radice, G., Takeichi, M. & Chisaka, O. Adhesive subdivisions intrinsic to the epithelial somites. Dev. Biol. 215, 182–189 (1999).
Bessho, Y. et al. Dynamic expression and essential functions of Hes7 in somite segmentation. Genes. Dev. 15, 2642–2647 (2001).
Sari, D. W. K. et al. Time-lapse observation of stepwise regression of Erk activity in zebrafish presomitic mesoderm. Sci. Rep. 8, 4335 (2018).
Naganathan, S. R. & Oates, A. C. Patterning and mechanics of somite boundaries in zebrafish embryos. Semin. Cell Dev. Biol. 107, 170–178 (2020).
Barrios, A. et al. Eph/Ephrin signaling regulates the mesenchymal-to-epithelial transition of the paraxial mesoderm during somite morphogenesis. Curr. Biol. 13, 1571–1582 (2003).
Watanabe, T., Sato, Y., Saito, D., Tadokoro, R. & Takahashi, Y. EphrinB2 coordinates the formation of a morphological boundary and cell epithelialization during somite segmentation. Proc. Natl Acad. Sci. USA 106, 7467–7472 (2009).
Jülich, D., Mould, A. P., Koper, E. & Holley, S. A. Control of extracellular matrix assembly along tissue boundaries via integrin and Eph/Ephrin signaling. Development 136, 2913–2921 (2009).
Koshida, S. et al. Integrin-α5-dependent fibronectin accumulation for maintenance of somite boundaries in zebrafish embryos. Dev. Cell 8, 587–598 (2005).
Nakaya, Y., Kuroda, S., Katagiri, Y. T., Kaibuchi, K. & Takahashi, Y. Mesenchymal-epithelial transition during somitic segmentation is regulated by differential roles of Cdc42 and Rac1. Dev. Cell 7, 425–438 (2004).
Martins, G. G. et al. Dynamic 3D cell rearrangements guided by a fibronectin matrix underlie somitogenesis. PLoS ONE 4, e7429 (2009).
Rifes, P. et al. Redefining the role of ectoderm in somitogenesis: a player in the formation of the fibronectin matrix of presomitic mesoderm. Development 134, 3155–3165 (2007).
Rifes, P. & Thorsteinsdóttir, S. Extracellular matrix assembly and 3D organization during paraxial mesoderm development in the chick embryo. Dev. Biol. 368, 370–381 (2012).
Rowton, M. et al. Regulation of mesenchymal-to-epithelial transition by PARAXIS during somitogenesis. Dev. Dyn. 242, 1332–1344 (2013).
Sánchez, R. S. & Sánchez, S. S. Paraxis is required for somite morphogenesis and differentiation in Xenopus laevis. Dev. Dyn. 244, 973–987 (2015).
Jülich, D. et al. Cross-scale integrin regulation organizes ECM and tissue topology. Dev. Cell 34, 33–44 (2015).
Chal, J., Guillot, C. & Pourquié, O. PAPC couples the segmentation clock to somite morphogenesis by regulating N-cadherin-dependent adhesion. Development 144, 664–676 (2017).
McMillen, P., Chatti, V., Jülich, D. & Holley, S. A. A sawtooth pattern of cadherin 2 stability mechanically regulates somite morphogenesis. Curr. Biol. 26, 542–549 (2016).
Rhee, J., Takahashi, Y., Saga, Y., Wilson-Rawls, J. & Rawls, A. The protocadherin papc is involved in the organization of the epithelium along the segmental border during mouse somitogenesis. Dev. Biol. 254, 248–261 (2003).
Nelemans, B. K. A., Schmitz, M., Tahir, H., Merks, R. M. H. & Smit, T. H. Somite division and new boundary formation by mechanical strain. iScience 23, 100976 (2020).
Adhyapok, P. et al. A mechanical model of early somite segmentation. iScience 24, 102317 (2021).
Naganathan, S. R., Popović, M. & Oates, A. C. Left-right symmetry of zebrafish embryos requires somite surface tension. Nature 605, 516–521 (2022). Here, the authors demonstrate that initially imprecise somites are progressively adjusted by surface tension to achieve bilateral symmetry in zebrafish and show that the adjustment is independent of the molecular clock, highlighting roles of mechanics in achieving precise tissue shapes.
Vilhais-Neto, G. C. et al. Rere controls retinoic acid signalling and somite bilateral symmetry. Nature 463, 953–957 (2010).
Ishimatsu, K. et al. Size-reduced embryos reveal a gradient scaling-based mechanism for zebrafish somite formation. Development 145, dev161257 (2018).
Eckalbar, W. L., Fisher, R. E., Rawls, A. & Kusumi, K. Scoliosis and segmentation defects of the vertebrae. Wiley Interdiscip. Rev. Dev. Biol. 1, 401–423 (2012).
Alexander, P. G. & Tuan, R. S. Role of environmental factors in axial skeletal dysmorphogenesis. Birth Defects Res. C. Embryo Today 90, 118–132 (2010).
Offiah, A. et al. Pilot assessment of a radiologic classification system for segmentation defects of the vertebrae. Am. J. Med. Genet. A 152A, 1357–1371 (2010).
Hou, D., Kang, N., Yin, P. & Hai, Y. Abnormalities associated with congenital scoliosis in high-altitude geographic regions. Int. Orthop. 42, 575–581 (2018).
Acknowledgements
This work was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the NIH under award numbers 5R01HD085121 (to O.P.) and K99HD111689 (to Y.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
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Miao, Y., Pourquié, O. Cellular and molecular control of vertebrate somitogenesis. Nat Rev Mol Cell Biol (2024). https://doi.org/10.1038/s41580-024-00709-z
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DOI: https://doi.org/10.1038/s41580-024-00709-z
