Axial Stem Cells and the Formation of the Vertebrate Body

  • André Dias
  • Rita AiresEmail author
Part of the Learning Materials in Biosciences book series (LMB)


Development of a whole multicellular complex organism from a single cell is not only an evolutionary triumph, but also the most daunting and formidable of tasks. The organism’s entire body plan is laid down in a series of intricate and interconnected events that comprise various levels of organization, from intracellular processes to vast morphogenetic tissue movements. This means that the embryo’s early symmetries must be gradually broken and that most of the initial cell potency needs to be progressively lost so that the body can increase in complexity and, ultimately, achieve its final form. In this chapter, using the mouse embryo as the chief model organism, we will address the formation of the vertebrate embryo from the perspective of the axial progenitor cells that are responsible for generating and patterning the tissues that will compose the postoccipital body structures.


Axial progenitors Neuro-mesodermal progenitors Stem cells Axial elongation Vertebrate body axis Gastrulation Embryo-like structures 



The authors would like to thank Moisés Mallo for the helpful insights, comments, and suggestions to this chapter; and to the remaining members of the Mallo lab for all the unparalled support and constant companionship.


  1. 1.
    Arnold SJ, Robertson EJ. Making a commitment: cell lineage allocation and axis patterning in the early mouse embryo. Nat Rev Mol Cell Biol. 2009;10(2):91–103.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Rossant J, Tam PPL. Blastocyst lineage formation, early embryonic asymmetries and axis patterning in the mouse. Development. 2009;136(5):701–13.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Takaoka K, Hamada H. Cell fate decisions and axis determination in the early mouse embryo. Development. 2012;139(1):3–14.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Tam PPL, Loebel DAF. Gene function in mouse embryogenesis: get set for gastrulation. Nat Rev Genet. 2007;8(May):368–81.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Shahbazi MN, Zernicka-Goetz M. Deconstructing and reconstructing the mouse and human early embryo. Nat Cell Biol. 2018;20(8):878–87.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Morkel M, Huelsken J, Wakamiya M, Ding J, van de Wetering M, Clevers H, et al. Beta-catenin regulates Cripto- and Wnt3-dependent gene expression programs in mouse axis and mesoderm formation. Development. 2003;130(25):6283–94.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Tam PP, Loebel DA, Tanaka SS. Building the mouse gastrula: signals, asymmetry and lineages. Curr Opin Genet Dev. 2006;16(4):419–25.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Wolpert L, RSP B, Brockes J, Jessell TM, Lawrence P, Meyerowitz E. Principles of development. 1st ed. London: Oxford University Press; 1998.Google Scholar
  9. 9.
    Varlet I, Collignon J, Robertson EJ. Nodal expression in the primitive endoderm is required for specification of the anterior axis during mouse gastrulation. Development. 1997;124(5):1033–44.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Conlon FL, Lyons KM, Takaesu N, Barth KS, Kispert A, Herrmann B, et al. A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse. Development. 1994;120(7):1919–28.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Barrow JR, Howell WD, Rule M, Hayashi S, Thomas KR, Capecchi MR, et al. Wnt3 signaling in the epiblast is required for proper orientation of the anteroposterior axis. Dev Biol. 2007;312(1):312–20.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Liu P, Wakamiya M, Shea MJ, Albrecht U, Behringer RR, Bradley A. Requirement for Wnt3 in vertebrate axis formation. Nat Genet. 1999;22(4):361–5.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Huelsken J, Vogel R, Brinkmann V, Erdmann B, Birchmeier C, Birchmeier W. Requirement for beta-catenin in anterior-posterior axis formation in mice. J Cell Biol. 2000;148(3):567–78.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Tam PP, Behringer RR. Mouse gastrulation: the formation of a mammalian body plan. Mech Dev. 1997;68(1–2):3–25.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Sun X, Meyers EN, Lewandoski M, Martin GR. Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo. Genes Dev. 1999;13(14):1834–46.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Ramkumar N, Omelchenko T, Silva-Gagliardi NF, McGlade CJ, Wijnholds J, Anderson KV. Crumbs2 promotes cell ingression during the epithelial-to-mesenchymal transition at gastrulation. Nat Cell Biol. 2016;18(12):1281–91.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Ben-Haim N, Lu C, Guzman-Ayala M, Pescatore L, Mesnard D, Bischofberger M, et al. The nodal precursor acting via activin receptors induces mesoderm by maintaining a source of its convertases and BMP4. Dev Cell. 2006;11(3):313–23.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Pfister S, Steiner KA, Tam PPL. Gene expression pattern and progression of embryogenesis in the immediate post-implantation period of mouse development. Gene Expr Patterns. 2007;7(5):558–73.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Robb L, Tam PPL. Gastrula organiser and embryonic patterning in the mouse. Semin Cell Dev Biol. 2004;15(5):543–54.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Tortelote GG, Rivera-Pérez J. a. Wnt3 function in the epiblast is required for the maintenance but not the initiation of gastrulation in mice. Dev Biol. 2013;130(29):9492–9.Google Scholar
  21. 21.
    Williams M, Burdsal C, Periasamy A, Lewandoski M, Sutherland A. Mouse primitive streak forms in situ by initiation of epithelial to mesenchymal transition without migration of a cell population. Dev Dyn. 2012;241(2):270–83.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Sutherland AE. Tissue morphodynamics shaping the early mouse embryo. Semin Cell Dev Biol. 2016;55:89–98.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Stern CD, Charité J, Deschamps J, Duboule D, Durston AJ, Kmita M, et al. Head-tail patterning of the vertebrate embryo: one, two or many unresolved problems? Int J Dev Biol. 2006;50(1):3–15.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Tam PPL, Tan SS. The somitogenetic potential of cells in the primitive streak and the tail bud of the organogenesis-stage mouse embryo. Development. 1992;115(3):703–15.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Wilson V, Olivera-Martinez I, Storey KG. Stem cells, signals and vertebrate body axis extension. Development. 2009;136(12):2133.Google Scholar
  26. 26.
    Martinez Arias A, Steventon B. On the nature and function of organizers. Development. 2018;145(5)Google Scholar
  27. 27.
    Spemann H, Mangold H. Über Induktion von Embryonalanlagen durch Implantation artfremder Organisatoren. Arch für Mikroskopische Anat und Entwicklungsmechanik. 1924;100(3-4):599–638.Google Scholar
  28. 28.
    Waddington C. Experiments on the development of chick and duck embryos, cultivated in vitro. Phil Trans R Soc Lond B. 1932;221:179–230.Google Scholar
  29. 29.
    Waddington CH. Principles of embryology. London: Georg Allen Unwin; 1954.Google Scholar
  30. 30.
    Beddington RSP. Induction of a second neural axis by the mouse node. Development. 1994;120(3):613–20.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Aires R, Dias A, Mallo M. Deconstructing the molecular mechanisms shaping the vertebrate body plan. Curr Opin Cell Biol. 2018;55:81–6.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Holmdahl DE. Experimentelle Untersuchungen uber die Lage der Grenze primarer und sekundarer Korperentwicklung beim Huhn. Anat Anz. 1925;59:393–6.Google Scholar
  33. 33.
    Catala M, Teillet MA, Le Douarin NM. Organization and development of the tail bud analyzed with the quail-chick chimaera system. Mech Dev. 1995;51(1):51–65.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Cambray N, Wilson V. Two distinct sources for a population of maturing axial progenitors. Development. 2007;134(15):2829–40.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Griffith CM, Wiley MJ, Sanders EJ. Anatomy and embryology review article the vertebrate tail bud: three germ layers from one tissue. Anat Embryol (Berl). 1992;185:101–13.Google Scholar
  36. 36.
    Schoenwolf GC. Tail (end) bud contributions to the posterior region of the chick embryo. J Exp Zool. 1977;201(2):227–45.Google Scholar
  37. 37.
    Wymeersch FJ, Skylaki S, Huang Y, Watson JA, Economou C, Marek-Johnston C, et al. Transcriptionally dynamic progenitor populations organised around a stable niche drive axial patterning. Development. 2019;146(1):1–16.Google Scholar
  38. 38.
    Tzouanacou E, Amélie W, Filip JW, Valerie W, Jean-François N. Redefining the progression of lineage segregations during mammalian embryogenesis by clonal analysis. Dev Cell. 2009;17:365–76.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Koch F, Scholze M, Wittler L, Schifferl D, Sudheer S, Grote P, et al. Antagonistic activities of Sox2 and brachyury control the fate choice of neuro-mesodermal progenitors. Dev Cell. 2017;42(5):514–526.e7.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Wymeersch FJ, Huang Y, Blin G, Cambray N, Wilkie R, Wong FCK, et al. Position-dependent plasticity of distinct progenitor types in the primitive streak. elife. 2016;5(JANUARY2016):1–28.Google Scholar
  41. 41.
    Martin BL, Kimelman D. Canonical Wnt signaling dynamically controls multiple stem cell fate decisions during vertebrate body formation. Dev Cell. 2012;22(1):223–32.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Olivera-Martinez I, Harada H, Halley PA, Storey KG. Loss of FGF-dependent mesoderm identity and rise of endogenous retinoid signalling determine cessation of body axis elongation. PLoS Biol. 2012;10(10):e1001415.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Tsakiridis A, Huang Y, Blin G, Skylaki S, Wymeersch F, Osorno R, et al. Distinct Wnt-driven primitive streak-like populations reflect in vivo lineage precursors. Development. 2014;141(6):1209–21.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Rodrigo Albors A, Halley PA, Storey KG. Lineage tracing of axial progenitors using Nkx1-2CreER T2 mice defines their trunk and tail contributions. Development. 2018;145(19)Google Scholar
  45. 45.
    Henrique D, Abranches E, Verrier L, Storey KG. Neuromesodermal progenitors and the making of the spinal cord. Development. 2015;142(17):2864–75.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Cambray N, Wilson V. Axial progenitors with extensive potency are localised to the mouse chordoneural hinge. Development. 2002;129(20):4855–66.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Gouti M, Delile J, Stamataki D, Kleinjung J, Wilson V, Briscoe J, et al. A gene regulatory network balances neural and mesoderm specification during vertebrate trunk development. Dev Cell. 2017;41(3):243–261.e7.PubMedPubMedCentralGoogle Scholar
  48. 48.
    DeVeale B, Brokhman I, Mohseni P, Babak T, Yoon C, Lin A, et al. Oct4 is required ∼E7.5 for proliferation in the primitive streak. PLoS Genet. 2013;9(11)Google Scholar
  49. 49.
    Osorno R, Tsakiridis A, Wong F, Cambray N, Economou C, Wilkie R, et al. The developmental dismantling of pluripotency is reversed by ectopic Oct4 expression. Development. 2012;139(13):2288–98.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell [Internet]. 2006 [cited 2014 May 23];126(4):663–76.Google Scholar
  51. 51.
    Aires R, Jurberg AD, Leal F, Nóvoa A, Cohn MJ, Mallo M. Oct4 is a key regulator of vertebrate trunk length diversity. Dev Cell. 2016;38(3):262–74.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Economou C, Tsakiridis A, Wymeersch FJ, Gordon-Keylock S, Dewhurst RE, Fisher D, et al. Intrinsic factors and the embryonic environment influence the formation of extragonadal teratomas during gestation early development. BMC Dev Biol. 2015;15(1):1–15.Google Scholar
  53. 53.
    Shyh-Chang N, Daley GQ. Lin28: primal regulator of growth and metabolism in stem cells. Cell Stem Cell. 2013;12(4):395–406.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Aires R, de Lemos L, Nóvoa A, Jurberg AD, Mascrez B, Duboule D, et al. Tail bud progenitor activity relies on a network comprising Gdf11, Lin28, and Hox13 genes. Dev Cell. 2019;48(3):383–395.e8.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Robinton DA, Chal J, Lummertz da Rocha E, Han A, Yermalovich AV, Oginuma M, et al. The Lin28/let-7 pathway regulates the mammalian caudal body axis elongation program. Dev Cell. 2019;48(3):396–405.e3.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Tahara N, Kawakami H, Chen KQ, Anderson A, Yamashita Peterson M, Gong W, et al. Sall4 regulates neuromesodermal progenitors and their descendants during body elongation in mouse embryos. Development. 2019;146(14):dev177659.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Parr BA, Shea MJ, Vassileva G, McMahon AP. Mouse Wnt genes exhibit discrete domains of expression in the early embryonic CNS and limb buds. Development. 1993;119(1):247–61.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Olivera-Martinez I, Storey KG. Wnt signals provide a timing mechanism for the FGF-retinoid differentiation switch during vertebrate body axis extension. Development. 2007;134(11):2125–35.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Takada S, Stark KL, Shea MJ, Vassileva G, McMahon JA, McMahon AP. Wnt-3a regulates somites and tailbud formation in the mouse embryo. Genes Dev. 1994;8:174–89.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Aulehla A, Wiegraebe W, Baubet V, Wahl MB, Deng C, Taketo M, et al. A beta-catenin gradient links the clock and wavefront systems in mouse embryo segmentation. Nat Cell Biol. 2008;10(2):186–93.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Yoshikawa Y, Fujimori T, McMahon AP, Takada S. Evidence that absence of Wnt-3a signaling promotes neuralization instead of paraxial mesoderm development in the mouse. Dev Biol. 1997;183(2):234–42.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Jurberg AD, Aires R, Nóvoa A, Rowland JE, Mallo M. Compartment-dependent activities of Wnt3a/β-catenin signaling during vertebrate axial extension. Dev Biol. 2014;394(2):253–63.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Garriock RJ, Chalamalasetty RB, Kennedy MW, Canizales LC, Lewandoski M, Yamaguchi TP. Lineage tracing of neuromesodermal progenitors reveals novel Wnt-dependent roles in trunk progenitor cell maintenance and differentiation. Development. 2015;142(9):1628–38.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Yamaguchi TP, Bradley A, McMahon AP, Jones S. A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo. Development. 1999;126(6):1211–23.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Aulehla A, Wehrle C, Brand-Saberi B, Kemler R, Gossler A, Kanzler B, et al. Wnt3a plays a major role in the segmentation clock controlling somitogenesis. Dev Cell. 2003;4(3):395–406.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Cunningham TJ, Kumar S, Yamaguchi TP, Duester G. Wnt8a and Wnt3a cooperate in the axial stem cell niche to promote mammalian body axis extension. Dev Dyn. 2015;244(6):797–807.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Ciruna B, Rossant J. FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak. Dev Cell. 2001;1(1):37–49.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Guo Q, Li JYH. Distinct functions of the major Fgf8 spliceform, before and during mouse gastrulation. Development. 2007;134(12):2251–60.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Wahl MB, Deng C, Lewandowski M, Pourquié O. FGF signaling acts upstream of the NOTCH and WNT signaling pathways to control segmentation clock oscillations in mouse somitogenesis. Development. 2007;134(22):4033–41.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Naiche LA, Holder N, Lewandoski M. FGF4 and FGF8 comprise the wavefront activity that controls somitogenesis. Proc Natl Acad Sci. 2011;108(10):4018–23.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Boulet AM, Capecchi MR. Signaling by FGF4 and FGF8 is required for axial elongation of the mouse embryo. Dev Biol. 2012;371(2):235–45.PubMedPubMedCentralGoogle Scholar
  72. 72.
    van Rooijen C, Simmini S, Bialecka M, Neijts R, van de Ven C, Beck F, et al. Evolutionarily conserved requirement of Cdx for post-occipital tissue emergence. Development. 2012;139(14):2576–83.PubMedPubMedCentralGoogle Scholar
  73. 73.
    van den Akker E, Forlani S, Chawengsaksophak K, de Graaff W, Beck F, Meyer BI, et al. Cdx1 and Cdx2 have overlapping functions in anteroposterior patterning and posterior axis elongation. Development. 2002;129(9):2181–93.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Young T, Rowland JE, van de Ven C, Bialecka M, Novoa A, Carapuco M, et al. Cdx and Hox genes differentially regulate posterior axial growth in mammalian embryos. Dev Cell. 2009;17(4):516–26.PubMedPubMedCentralGoogle Scholar
  75. 75.
    van Nes J, de Graaff W, Lebrin F, Gerhard M, Beck F, Deschamps J. The Cdx4 mutation affects axial development and reveals an essential role of Cdx genes in the ontogenesis of the placental labyrinth in mice. Development. 2006;133(3):419–28.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Amin S, Neijts R, Simmini S, van Rooijen C, Tan SC, Kester L, et al. Cdx and T Brachyury co-activate growth signaling in the embryonic axial progenitor niche. Cell Rep. 2016;17(12):3165–77.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Kessel M, Gruss P. Homeotic transformations of murine vertebrae and concomitant alteration of Hox codes induced by retinoic acid. Cell. 1991;67(1894)Google Scholar
  78. 78.
    Kessel M. Respecification of vertebral identities by retinoic acid. Development. 1992;115(2):487–501.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Berenguer M, Lancman JJ, Cunningham TJ, Dong PDS, Duester G. Mouse but not zebrafish requires retinoic acid for control of neuromesodermal progenitors and body axis extension. Dev Biol. 2018;441(1):127–31.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Steventon B, Martinez AA. Evo-engineering and the cellular and molecular origins of the vertebrate spinal cord. Dev Biol. 2017;432(1):3–13.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Niederreither K, Subbarayan V, Chambon P, Dollé P. Embryonic retinoic acid synthesis is essential for early mouse post- implantation development letter. Nat Genet. 1999;21:444–8.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Mic FA, Haselbeck RJ, Cuenca AE, Duester G. Novel retinoic acid generating activities in the neural tube and heart identified by conditional rescue of Raldh2 null mutant mice. Development. 2002;129(9):2271–82.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Niederreither K, Vermot J, Schuhbaur B, Chambon P, Dollé P. Embryonic retinoic acid synthesis is required for forelimb growth and anteroposterior patterning in the mouse. Development. 2002;129(15):3563–74.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Abu-Abed S, Dolle P, Metzger D, Wood C, MacLean G, Chambon P, et al. Developing with lethal RA levels: genetic ablation of Rarg can restore the viability of mice lacking Cyp26a1. Development. 2003;130(7):1449–59.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Abu-Abed S. The retinoic acid-metabolizing enzyme, CYP26A1, is essential for normal hindbrain patterning, vertebral identity, and development of posterior structures. Genes Dev. 2001;15(2):226–40.PubMedPubMedCentralGoogle Scholar
  86. 86.
    Carvalho JE, Theodosiou M, Chen J, Chevret P, Alvarez S, De Lera AR, et al. Lineage-specific duplication of amphioxus retinoic acid degrading enzymes (CYP26) resulted in sub-functionalization of patterning and homeostatic roles. BMC Evol Biol. 2017;17(1):1–23.Google Scholar
  87. 87.
    Cunningham TJ, Brade T, Sandell LL, Lewandoski M, Trainor PA, Colas A, et al. Retinoic acid activity in undifferentiated neural progenitors is sufficient to fulfill its role in restricting Fgf8 expression for somitogenesis. PLoS One. 2015;10(9):1–15.Google Scholar
  88. 88.
    Zhao X, Duester G. Effect of retinoic acid signaling on Wnt/β-catenin and FGF signaling during body axis extension. Gene Expr Patterns. 2009;9(6):430–5.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Yamaguchi TP, Takada S, Yoshikawa Y, Wu N, McMahon AP. T (Brachyury) is a direct target of Wnt3a during paraxial mesoderm specification. Genes Dev. 1999;13(24):3185–90.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Wilson V, Beddington R. Expression of T protein in the primitive streak is necessary and sufficient for posterior mesoderm movement and somite differentiation. Dev Biol. 1997;192(1):45–58.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Stott D, Kispert A, Herrmann BG. Rescue of the tail defect of Brachyury mice. Genes Dev. 1993;7(2):197–203.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Galceran J, Hsu SC, Grosschedl R. Rescue of a Wnt mutation by an activated form of LEF-1: regulation of maintenance but not initiation of Brachyury expression. Proc Natl Acad Sci U S A. 2001;98(15):8668–73.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Nowotschin S, Ferrer-Vaquer A, Concepcion D, Papaioannou VE, Hadjantonakis AK. Interaction of Wnt3a, Msgn1 and Tbx6 in neural versus paraxial mesoderm lineage commitment and paraxial mesoderm differentiation in the mouse embryo. Dev Biol. 2012;367(1):1–14.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Chalamalasetty RB, Dunty WC, Biris KK, Ajima R, Iacovino M, Beisaw A, et al. The Wnt3a/β-catenin target gene Mesogenin1 controls the segmentation clock by activating a Notch signalling program. Nat Commun. 2011;2(1):312–90.Google Scholar
  95. 95.
    Chapman DL, Papaioannou VE. Three neural tubes in mouse embryos with mutations in the T-box gene Tbx6. Nature. 1998;391(1991):695–7.PubMedPubMedCentralGoogle Scholar
  96. 96.
    Chapman DL, Agulnik I, Hancock S, Silver LM, Papaioannou VE. Tbx6, a mouse T-box gene implicated in paraxial mesoderm formation at gastrulation. Dev Biol. 1996;180(2):534–42.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Javali A, Misra A, Leonavicius K, Acharyya D, Vyas B, Sambasivan R. Co-expression of Tbx6 and Sox2 identifies a novel transient neuromesoderm progenitor cell state. Development. 2017;144(24):4522–9.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Takemoto T, Uchikawa M, Kamachi Y, Kondoh H. Convergence of Wnt and FGF signals in the genesis of posterior neural plate through activation of the Sox2 enhancer N-1. Development. 2006;133(2):297–306.PubMedPubMedCentralGoogle Scholar
  99. 99.
    Takemoto T, Uchikawa M, Yoshida M, Bell DM, Lovell-Badge R, Papaioannou VE, et al. Tbx6-dependent Sox2 regulation determines neural or mesodermal fate in axial stem cells. Nature. 2011;470(7334):394–8.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Deschamps J, van Nes J. Developmental regulation of the Hox genes during axial morphogenesis in the mouse. Development. 2005;132(13):2931–42.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Chawengsaksophak K, James R, Hammond VE, Köntgen F, Beck F. Homeosis and intestinal tumours in Cdx2 mutant mice. Nature. 1997;386(6620):84–7.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Chawengsaksophak K, de Graaff W, Rossant J, Deschamps J, Beck F. Cdx2 is essential for axial elongation in mouse development. Proc Natl Acad Sci U S A. 2004;101(20):7641–5.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Subramanian V, Meyer BI, Gruss P. Disruption of the murine homeobox gene Cdx1 affects axial skeletal identities by altering the mesodermal expression domains of Hox genes. Cell. 1995;83(4):641–53.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Neijts R, Amin S, van Rooijen C, Deschamps J. Cdx is crucial for the timing mechanism driving colinear Hox activation and defines a trunk segment in the Hox cluster topology. Dev Biol. 2017;422(2):146–54.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Gaunt SJ, George M, Paul YL. Direct activation of a mouse Hoxd11 axial expression enhancer by Gdf11/Smad signalling. Dev Biol. 2013;383(1):52–60.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Mcpherron AC, Lawler AM, Lee S. Regulation of anterior / posterior patterning of the axial skeleton by growth/differentiation factor 11. Nature. 1999;22(july):1–5.Google Scholar
  107. 107.
    Jurberg AD, Aires R, Varela-Lasheras I, Nóvoa A, Mallo M. Switching axial progenitors from producing trunk to tail tissues in vertebrate embryos. Dev Cell. 2013;25(5):451–62.PubMedPubMedCentralGoogle Scholar
  108. 108.
    McPherron AC, Huynh TV, Lee SJ. Redundancy of myostatin and growth/differentiation factor 11 function. BMC Dev Biol. 2009;9(1):1–9.Google Scholar
  109. 109.
    Duboule D, Dollé P. The structural and functional organization of the murine HOX gene family resembles that of Drosophila homeotic genes. EMBO J. 1989;8(5):1497–505.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Kmita M, Duboule D. Organizing axes in time and space; 25 years of colinear tinkering. Science (80-). 2003;301(5631):331–3.Google Scholar
  111. 111.
    Forlani S. Acquisition of Hox codes during gastrulation and axial elongation in the mouse embryo. Development. 2003;130(16):3807–19.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Iimura T, Pourquié O. Collinear activation of Hoxb genes during gastrulation is linked to mesoderm cell ingression. Nature. 2006;442(7102):568–71.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Deschamps J, Duboule D. Embryonic timing, axial stem cells, chromatin dynamics, and the Hox clock. Genes Dev. 2017;31(14):1406–16.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Nakashima M, Toyono T, Akamine A, Joyner A. Expression of growth/differentiation factor 11, a new member of the BMP/TGFbeta superfamily during mouse embryogenesis. Mech Dev. 1999;80(2):185–9.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Oh SP, Li E. The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse. Genes Dev. 1997;11(14):1812–26.PubMedPubMedCentralGoogle Scholar
  116. 116.
    Denans N, Iimura T, Pourquié O. Hox genes control vertebrate body elongation by collinear Wnt repression. elife. 2015;2015(4):1–33.Google Scholar
  117. 117.
    Economides KD, Zeltser L, Capecchi MR. Hoxb13 mutations cause overgrowth of caudal spinal cordand tail vertebrae. Dev Biol. 2003;256(2):317–30.PubMedPubMedCentralGoogle Scholar
  118. 118.
    van de Ven C, Bialecka M, Neijts R, Young T, Rowland JE, Stringer EJ, et al. Concerted involvement of Cdx/Hox genes and Wnt signaling in morphogenesis of the caudal neural tube and cloacal derivatives from the posterior growth zone. Development. 2011;138(16):3451–62.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Gomez C, Özbudak EM, Wunderlich J, Baumann D, Lewis J, Pourquié O. Control of segment number in vertebrate embryos. Nature. 2008;454(7202):335–9.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Matsubara Y, Hirasawa T, Egawa S, Hattori A, Suganuma T, Kohara Y, et al. Anatomical integration of the sacral-hindlimb unit coordinated by GDF11 underlies variation in hindlimb positioning in tetrapods. Nat Ecol Evol. 2017;1(9):1392–9.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Gouti M, Tsakiridis A, Wymeersch FJ, Huang Y, Kleinjung J, Wilson V, et al. In vitro generation of neuromesodermal progenitors reveals distinct roles for wnt signalling in the specification of spinal cord and paraxial mesoderm identity. PLoS Biol. 2014;12(8)Google Scholar
  122. 122.
    Turner DA, Hayward PC, Baillie-Johnson P, Rue P, Broome R, Faunes F, et al. Wnt/ -catenin and FGF signalling direct the specification and maintenance of a neuromesodermal axial progenitor in ensembles of mouse embryonic stem cells. Development. 2014;141(22):4243–53.PubMedPubMedCentralGoogle Scholar
  123. 123.
    Tesar PJ, Chenoweth JG, Brook FA, Davies TJ, Evans EP, Mack DL, et al. New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature. 2007;448(7150):196–9.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Edri S, Hayward P, Jawaid W, Martinez AA. Neuro-mesodermal progenitors (NMPs): a comparative study between pluripotent stem cells and embryo-derived populations. Development. 2019;146(12)Google Scholar
  125. 125.
    Edri S, Hayward P, Baillie-Johnson P, Steventon BJ, Martinez AA. An epiblast stem cell-derived multipotent progenitor population for axial extension. Development. 2019;146(10)Google Scholar
  126. 126.
    Lippmann ES, Williams CE, Ruhl DA, Estevez-silva MC, Chapman ER, Coon JJ, et al. Deterministic HOX Patterning in Human Pluripotent Stem Cell-Derived Neuroectoderm. Stem Cell Reports. 2015;4(4):632–44.PubMedPubMedCentralGoogle Scholar
  127. 127.
    Simunovic M, Brivanlou AH. Embryoids, organoids and gastruloids: new approaches to understanding embryogenesis. Dev. 2017;144(6):976–85.Google Scholar
  128. 128.
    Harrison SE, Sozen B, Christodoulou N, Kyprianou C, Zernicka-Goetz M. Assembly of embryonic and extraembryonic stem cells to mimic embryogenesis in vitro. Science (80-). 2017;356(6334)Google Scholar
  129. 129.
    Rivron NC, Frias-Aldeguer J, Vrij EJ, Boisset JC, Korving J, Vivié J, et al. Blastocyst-like structures generated solely from stem cells. Nature. 2018;557(7703):106–11.PubMedPubMedCentralGoogle Scholar
  130. 130.
    Sozen B, Amadei G, Cox A, Wang R, Na E, Czukiewska S, et al. Self-assembly of embryonic and two extra-embryonic stem cell types into gastrulating embryo-like structures. Nat Cell Biol. 2018;20(8):979–89.PubMedPubMedCentralGoogle Scholar
  131. 131.
    Turner DA, Girgin M, Alonso-Crisostomo L, Trivedi V, Baillie-Johnson P, Glodowski CR, et al. Anteroposterior polarity and elongation in the absence of extraembryonic tissues and of spatially localised signalling in gastruloids: mammalian embryonic organoids. Dev. 2017;144(21):3894–906.Google Scholar
  132. 132.
    Beccari L, Moris N, Girgin M, Turner DA, Baillie-Johnson P, Cossy AC, et al. Multi-axial self-organization properties of mouse embryonic stem cells into gastruloids. Nature. 2018;562(7726):272–6.PubMedPubMedCentralGoogle Scholar
  133. 133.
    Mulas C, Kalkan T, von Meyenn F, Leitch HG, Nichols J, Smith A. Correction: defined conditions for propagation and manipulation of mouse embryonic stem cells. Development. 2019;146(7)
  134. 134.
    Peng G, Suo S, Cui G, Yu F, Wang R, Chen J, et al. Molecular architecture of lineage allocation and tissue organization in early mouse embryo. Nature. 2019;572(7770):528–32.PubMedPubMedCentralGoogle Scholar
  135. 135.
    Pijuan-Sala B, Griffiths JA, Guibentif C, Hiscock TW, Jawaid W, Calero-Nieto FJ, et al. A single-cell molecular map of mouse gastrulation and early organogenesis. Nature. 2019;566(7745):490–5.PubMedPubMedCentralGoogle Scholar
  136. 136.
    Cao J, Spielmann M, Qiu X, Huang X, Ibrahim DM, Hill AJ, et al. The single-cell transcriptional landscape of mammalian organogenesis. Nature. 2019;566(7745):496–502.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Instituto Gulbenkian de CiênciaOeirasPortugal
  2. 2.DFG-Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität DresdenDresdenGermany

Personalised recommendations