A self-organization framework for symmetry breaking in the mammalian embryo


The mechanisms underlying the appearance of asymmetry between cells in the early embryo and consequently the specification of distinct cell lineages during mammalian development remain elusive. Recent experimental advances have revealed unexpected dynamics of and new complexity in this process. These findings can be integrated in a new unified framework that regards the early mammalian embryo as a self-organizing system.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Classic models for lineage segregation in the early mouse embryo.
Figure 2: The self-organization theory of early mammalian development.


  1. 1

    Rossant, J. & Tam, P. P. L. Emerging asymmetry and embryonic patterning in early mouse development. Dev. Cell 7, 155–164 (2004).

    CAS  PubMed  Google Scholar 

  2. 2

    Rossant, J. & Tam, P. P. L. Blastocyst lineage formation, early embryonic asymmetries and axis patterning in the mouse. Development 136, 701–713 (2009).

    CAS  PubMed  Google Scholar 

  3. 3

    Guo, G. et al. Resolution of cell fate decisions revealed by single-cell gene expression analysis from zygote to blastocyst. Dev. Cell 18, 675–685 (2010).

    CAS  PubMed  Google Scholar 

  4. 4

    Johnson, M. H. & Ziomek, C. A. The foundation of two distinct cell lineages within the mouse morula. Cell 24, 71–80 (1981).

    CAS  PubMed  Google Scholar 

  5. 5

    Graham, C. F. & Lehtonen, E. Formation and consequences of cell patterns in preimplantation mouse development. J. Embryol. Exp. Morphol. 49, 277–294 (1979).

    CAS  PubMed  Google Scholar 

  6. 6

    Fleming, T. P. A quantitative analysis of cell allocation to trophectoderm and inner cell mass in the mouse blastocyst. Dev. Biol. 119, 520–531 (1987).

    CAS  PubMed  Google Scholar 

  7. 7

    Hiiragi, T. & Solter, D. First cleavage plane of the mouse egg is not predetermined but defined by the topology of the two apposing pronuclei. Nature 430, 360–364 (2004).

    CAS  PubMed  Google Scholar 

  8. 8

    Motosugi, N., Bauer, T., Polanski, Z., Solter, D. & Hiiragi, T. Polarity of the mouse embryo is established at blastocyst and is not prepatterned. Gene. Dev. 19, 1081–1092 (2005).

    CAS  PubMed  Google Scholar 

  9. 9

    Louvet-Vallee, S., Vinot, S. & Maro, B. Mitotic spindles and cleavage planes are oriented randomly in the two-cell mouse embryo. Curr. Biol. 15, 464–469 (2005).

    CAS  PubMed  Google Scholar 

  10. 10

    Kurotaki, Y., Hatta, K., Nakao, K., Nabeshima, Y.-I. & Fujimori, T. Blastocyst axis is specified independently of early cell lineage but aligns with the ZP shape. Science 316, 719–723 (2007).

    CAS  PubMed  Google Scholar 

  11. 11

    Rossant, J. & Lis, W. T. Potential of isolated mouse inner cell masses to form trophectoderm derivatives in vivo. Dev. Biol. 70, 255–261 (1979).

    CAS  PubMed  Google Scholar 

  12. 12

    Rossant, J. & Vijh, K. M. Ability of outside cells from preimplantation mouse embryos to form inner cell mass derivatives. Dev. Biol. 76, 475–482 (1980).

    CAS  PubMed  Google Scholar 

  13. 13

    Driever, W. & Nüsslein-Volhard, C. A gradient of bicoid protein in Drosophila embryos. Cell 54, 83–93 (1988).

    CAS  PubMed  Google Scholar 

  14. 14

    Driever, W. & Nüsslein-Volhard, C. The bicoid protein determines position in the Drosophila embryo in a concentration-dependent manner. Cell 54, 95–104 (1988).

    CAS  Article  Google Scholar 

  15. 15

    Goldstein, B. & Hird, S. N. Specification of the anteroposterior axis in Caenorhabditis elegans. Development 122, 1467–1474 (1996).

    CAS  PubMed  Google Scholar 

  16. 16

    Speman, H. Embryonic development and induction. Am. J. Med. Sci. 196, 738 (1938).

    Google Scholar 

  17. 17

    Vincent, J. P., Oster, G. F. & Gerhart, J. C. Kinematics of gray crescent formation in Xenopus eggs: the displacement of subcortical cytoplasm relative to the egg surface. Dev. Biol. 113, 484–500 (1986).

    CAS  PubMed  Google Scholar 

  18. 18

    Dalcq, A. Introduction to General Embryology (Oxford Univ. Press, 1957).

    Google Scholar 

  19. 19

    Piotrowska, K. & Zernicka-Goetz, M. Role for sperm in spatial patterning of the early mouse embryo. Nature 409, 517–521 (2001).

    CAS  PubMed  Google Scholar 

  20. 20

    Piotrowska, K., Wianny, F., Pedersen, R. A. & Zernicka-Goetz, M. Blastomeres arising from the first cleavage division have distinguishable fates in normal mouse development. Development 128, 3739–3748 (2001).

    CAS  PubMed  Google Scholar 

  21. 21

    Gardner, R. Specification of embryonic axes begins before cleavage in normal mouse development. Development 128, 839–847 (2001).

    CAS  PubMed  Google Scholar 

  22. 22

    Piotrowska-Nitsche, K., Perea-Gomez, A., Haraguchi, S. & Zernicka-Goetz, M. Four-cell stage mouse blastomeres have different developmental properties. Development 132, 479–490 (2005).

    CAS  PubMed  Google Scholar 

  23. 23

    Gardner, R. Experimental analysis of second cleavage in the mouse. Hum. Reprod. 17, 3178–3189 (2002).

    CAS  PubMed  Google Scholar 

  24. 24

    Hiiragi, T. et al. Where do we stand now? Mouse early embryo patterning meeting in Freiburg, Germany (2005). Int. J. Dev. Biol. 50, 581–586 (2005).

    Google Scholar 

  25. 25

    Littwin, T. & Denker, H. W. Segregation during cleavage in the mammalian embryo? A critical comparison of whole-mount/CLSM and section immunohistochemistry casts doubts on segregation of axis-relevant leptin domains in the rabbit. Histochem. Cell Biol. 135, 553–570 (2011).

    CAS  PubMed  Google Scholar 

  26. 26

    Schulz, L. C. & Roberts, R. M. Dynamic changes in leptin distribution in the progression from ovum to blastocyst of the pre-implantation mouse embryo. Reproduction 141, 767–777 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Antczak, M. & Van Blerkom, J. Oocyte influences on early development: the regulatory proteins leptin and STAT3 are polarized in mouse and human oocytes and differentially distributed within the cells of the preimplantation stage embryo. Mol. Hum. Reprod. 3, 1067–1086 (1997).

    CAS  PubMed  Google Scholar 

  28. 28

    Antczak, M. & Van Blerkom, J. Temporal and spatial aspects of fragmentation in early human embryos: possible effects on developmental competence and association with the differential elimination of regulatory proteins from polarized domains. Hum. Reprod. 14, 429–447 (1999).

    CAS  PubMed  Google Scholar 

  29. 29

    Marikawa, Y. & Alarcon, V. B. Establishment of trophectoderm and inner cell mass lineages in the mouse embryo. Mol. Reprod. Dev. 76, 1019–1032 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Tarkowski, A. K. Experiments on the development of isolated blastomers of mouse eggs. Nature 184, 1286–1287 (1959).

    CAS  PubMed  Google Scholar 

  31. 31

    Tarkowski, A. K. & Wróblewska, J. Development of blastomeres of mouse eggs isolated at the 4- and 8-cell stage. J. Embryol. Exp. Morphol. 18, 155–180 (1967).

    CAS  PubMed  Google Scholar 

  32. 32

    Nishioka, N. et al. The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass. Dev. Cell 16, 398–410 (2009).

    CAS  PubMed  Google Scholar 

  33. 33

    Dietrich, J. E. & Hiiragi, T. Stochastic patterning in the mouse pre-implantation embryo. Development 134, 4219–4231 (2007).

    CAS  PubMed  Google Scholar 

  34. 34

    Ralston, A. & Rossant, J. Cdx2 acts downstream of cell polarization to cell-autonomously promote trophectoderm fate in the early mouse embryo. Dev. Biol. 313, 614–629 (2008).

    CAS  PubMed  Google Scholar 

  35. 35

    Plusa, B., Piliszek, A., Frankenberg, S., Artus, J. & Hadjantonakis, A. K. Distinct sequential cell behaviours direct primitive endoderm formation in the mouse blastocyst. Development 135, 3081–3091 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Ducibella, T. & Anderson, E. Cell shape and membrane changes in the eight-cell mouse embryo: prerequisites for morphogenesis of the blastocyst. Dev. Biol. 47, 45–58 (1975).

    CAS  PubMed  Google Scholar 

  37. 37

    Handyside, A. H. Distribution of antibody- and lectin-binding sites on dissociated blastomeres from mouse morulae: evidence for polarization at compaction. J. Embryol. Exp. Morphol. 60, 99–116 (1980).

    CAS  PubMed  Google Scholar 

  38. 38

    Louvet, S., Aghion, J., Santa-Maria, A., Mangeat, P. & Maro, B. Ezrin becomes restricted to outer cells following asymmetrical division in the preimplantation mouse embryo. Dev. Biol. 177, 568–579 (1996).

    CAS  PubMed  Google Scholar 

  39. 39

    Vinot, S. et al. Asymmetric distribution of PAR proteins in the mouse embryo begins at the 8-cell stage during compaction. Dev. Biol. 282, 307–319 (2005).

    CAS  PubMed  Google Scholar 

  40. 40

    Stephenson, R. O., Yamanaka, Y. & Rossant, J. Disorganized epithelial polarity and excess trophectoderm cell fate in preimplantation embryos lacking E-cadherin. Development 137, 3383–3391 (2010).

    CAS  PubMed  Google Scholar 

  41. 41

    Dard, N., Louvet-Vallée, S. & Maro, B. Orientation of mitotic spindles during the 8- to 16-cell stage transition in mouse embryos. PLoS ONE 4, e8171 (2009).

    PubMed  PubMed Central  Google Scholar 

  42. 42

    Bischoff, M., Parfitt, D.-E. & Zernicka-Goetz, M. Formation of the embryonic–abembryonic axis of the mouse blastocyst: relationships between orientation of early cleavage divisions and pattern of symmetric/asymmetric divisions. Development 135, 953–962 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Yamanaka, Y., Lanner, F. & Rossant, J. FGF signal-dependent segregation of primitive endoderm and epiblast in the mouse blastocyst. Development 137, 715–724 (2010).

    CAS  PubMed  Google Scholar 

  44. 44

    Morris, S. A. et al. Origin and formation of the first two distinct cell types of the inner cell mass in the mouse embryo. Proc. Natl Acad. Sci. USA 107, 6364–6369 (2010).

    CAS  PubMed  Google Scholar 

  45. 45

    Chazaud, C., Yamanaka, Y., Pawson, T. & Rossant, J. Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2–MAPK pathway. Dev. Cell 10, 615–624 (2006).

    CAS  PubMed  Google Scholar 

  46. 46

    Dietrich, J. E. & Hiiragi, T. Stochastic processes during mouse blastocyst patterning. Cells Tissues Organs 188, 46–51 (2008).

    PubMed  Google Scholar 

  47. 47

    Chambers, I. et al. Nanog safeguards pluripotency and mediates germline development. Nature 450, 1230–1234 (2007).

    CAS  PubMed  Google Scholar 

  48. 48

    Kalmar, T. et al. Regulated fluctuations in Nanog expression mediate cell fate decisions in embryonic stem cells. PLoS Biol. 7, e1000149 (2009).

    PubMed  PubMed Central  Google Scholar 

  49. 49

    Silva, J. & Smith, A. Capturing pluripotency. Cell 132, 532–536 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Kurimoto, K. et al. An improved single-cell cDNA amplification method for efficient high-density oligonucleotide microarray analysis. Nucleic Acids Res. 34, e42 (2006).

    PubMed  PubMed Central  Google Scholar 

  51. 51

    Tang, F. et al. mRNA-seq whole-transcriptome analysis of a single cell. Nature Methods 6, 377–382 (2009).

    CAS  PubMed  Google Scholar 

  52. 52

    Tang, F. et al. Tracing the derivation of embryonic stem cells from the inner cell mass by single-cell RNA-seq analysis. Cell Stem Cell 6, 468–478 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Tang, F. et al. Deterministic and stochastic allele specific gene expression in single mouse blastomeres. PLoS ONE 6, e21208 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Itzkovitz, S., Blat, I. C., Jacks, T., Clevers, H. & van Oudenaarden, A. Optimality in the development of intestinal crypts. Cell 148, 608–619 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Itzkovitz, S. et al. Single-molecule transcript counting of stem-cell markers in the mouse intestine. Nature Cell Biol. 14, 106–114 (2011).

    PubMed  Google Scholar 

  56. 56

    Raj, A., van den Bogaard, P., Rifkin, S. A., van Oudenaarden, A. & Tyagi, S. Imaging individual mRNA molecules using multiple singly labeled probes. Nature Methods 5, 877–879 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Raj, A., Rifkin, S. A., Andersen, E. & van Oudenaarden, A. Variability in gene expression underlies incomplete penetrance. Nature 463, 913–918 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Buganim, Y. et al. Single-cell expression analyses during cellular reprogramming reveal an early stochastic and a late hierarchic phase. Cell 150, 1209–1222 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Plachta, N., Bollenbach, T., Pease, S., Fraser, S. E. & Pantazis, P. Oct4 kinetics predict cell lineage patterning in the early mammalian embryo. Nature Cell Biol. 13, 117–123 (2011).

    CAS  PubMed  Google Scholar 

  60. 60

    Lorthongpanich, C., Doris, T. P. Y., Limviphuvadh, V., Knowles, B. B. & Solter, D. Developmental fate and lineage commitment of singled mouse blastomeres. Development 139, 3722–3731 (2012).

    CAS  PubMed  Google Scholar 

  61. 61

    Johnson, M. H. From mouse egg to mouse embryo: polarities, axes, and tissues. Annu. Rev. Cell Dev. Biol. 25, 483–512 (2009).

    CAS  PubMed  Google Scholar 

  62. 62

    Wennekamp, S. & Hiiragi, T. Stochastic processes in the development of pluripotency in vivo. Biotechnol. J. 7, 737–744 (2012).

    CAS  PubMed  Google Scholar 

  63. 63

    Müller, P. et al. Differential diffusivity of Nodal and Lefty underlies a reaction–diffusion patterning system. Science 336, 721–724 (2012).

    PubMed  PubMed Central  Google Scholar 

  64. 64

    Nakamura, T. et al. Generation of robust left–right asymmetry in the mouse embryo requires a self-enhancement and lateral-inhibition system. Dev. Cell 11, 495–504 (2006).

    CAS  PubMed  Google Scholar 

  65. 65

    Niwa, H. et al. Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation. Cell 123, 917–929 (2005).

    CAS  PubMed  Google Scholar 

  66. 66

    Honda, H., Motosugi, N., Nagai, T., Tanemura, M. & Hiiragi, T. Computer simulation of emerging asymmetry in the mouse blastocyst. Development 135, 1407–1414 (2008).

    CAS  PubMed  Google Scholar 

  67. 67

    To, T. L. & Maheshri, N. Noise can induce bimodality in positive transcriptional feedback loops without bistability. Science 327, 1142–1145 (2010).

    CAS  PubMed  Google Scholar 

  68. 68

    Chang, H. H., Hemberg, M., Barahona, M., Ingber, D. E. & Huang, S. Transcriptome-wide noise controls lineage choice in mammalian progenitor cells. Nature 453, 544–547 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Meilhac, S. M. et al. Active cell movements coupled to positional induction are involved in lineage segregation in the mouse blastocyst. Dev. Biol. 331, 210–221 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    McDole, K. & Zheng, Y. Generation and live imaging of an endogenous Cdx2 reporter mouse line. Genesis 50, 775–782 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Krzic, U., Gunther, S., Saunders, T. E., Streichan, S. J. & Hufnagel, L. Multiview light-sheet microscope for rapid in toto imaging. Nature Methods 9, 730–733 (2012).

    CAS  PubMed  Google Scholar 

  72. 72

    Tomer, R., Khairy, K., Amat, F. & Keller, P. J. Quantitative high-speed imaging of entire developing embryos with simultaneous multiview light-sheet microscopy. Nature Methods 9, 755–763 (2012).

    CAS  PubMed  Google Scholar 

  73. 73

    Camazine, S. et al. Self-Organization in Biological Systems (Princeton Univ. Press, 2003).

    Google Scholar 

  74. 74

    Krupinski, P., Chickarmane, V. & Peterson, C. Simulating the mammalian blastocyst — molecular and mechanical interactions pattern the embryo. PLoS Comput. Biol. 7, e1001128 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Shipley, R. J., Bonsall, M. B., Allwright, D. J. & Graham, C. F. Theoretical exploration of blastocyst morphogenesis. Int. J. Dev. Biol. 53, 447–457 (2009).

    PubMed  Google Scholar 

  76. 76

    Strumpf, D. et al. Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst. Development 132, 2093–2102 (2005).

    CAS  PubMed  Google Scholar 

  77. 77

    Nishioka, N. et al. Tead4 is required for specification of trophectoderm in pre-implantation mouse embryos. Mech. Dev. 125, 270–283 (2008).

    CAS  PubMed  Google Scholar 

  78. 78

    Yagi, R. et al. Transcription factor TEAD4 specifies the trophectoderm lineage at the beginning of mammalian development. Development 134, 3827–3836 (2007).

    CAS  PubMed  Google Scholar 

  79. 79

    Nichols, J. et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95, 379–391 (1998).

    CAS  PubMed  Google Scholar 

  80. 80

    Avilion, A. A. et al. Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev. 17, 126–140 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Chambers, I. et al. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113, 643–655 (2003).

    CAS  PubMed  Google Scholar 

  82. 82

    Mitsui, K. et al. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113, 631–642 (2003).

    CAS  PubMed  Google Scholar 

  83. 83

    Kang, M., Piliszek, A., Artus, J. & Hadjantonakis, A.-K. FGF4 is required for lineage restriction and salt-and-pepper distribution of primitive endoderm factors but not their initial expression in the mouse. Development 140, 267–279 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Tarkowski, A. K. Mouse chimaeras developed from fused eggs. Nature 190, 857–860 (1961).

    CAS  PubMed  Google Scholar 

  85. 85

    Mitalipov, S. M., Yeoman, R. R., Kuo, H.-C. & Wolf, D. P. Monozygotic twinning in rhesus monkeys by manipulation of in vitro-derived embryos. Biol. Reprod. 66, 1449–1455 (2002).

    CAS  PubMed  Google Scholar 

  86. 86

    Gärtner, K. & Baunack, E. Is the similarity of monozygotic twins due to genetic factors alone? Nature 292, 646–647 (1981).

    PubMed  Google Scholar 

  87. 87

    Gardner, R. L. Mouse chimeras obtained by the injection of cells into the blastocyst. Nature 220, 596–597 (1968).

    CAS  PubMed  Google Scholar 

  88. 88

    Bradley, A., Evans, M., Kaufman, M. H. & Robertson, E. Formation of germ-line chimaeras from embryo-derived teratocarcinoma cell lines. Nature 309, 255–256 (1984).

    CAS  PubMed  Google Scholar 

  89. 89

    Saetzler, K., Sonnenschein, C. & Soto, A. M. Systems biology beyond networks: generating order from disorder through self-organization. Semin. Cancer Biol. 21, 165–174 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Karsenti, E. Self-organization in cell biology: a brief history. Nature Rev. Mol. Cell Biol. 9, 255–262 (2008).

    CAS  Google Scholar 

  91. 91

    Sasai, Y. Cytosystems dynamics in self-organization of tissue architecture. Nature 493, 318–326 (2013).

    CAS  PubMed  Google Scholar 

  92. 92

    Clayton, E. et al. A single type of progenitor cell maintains normal epidermis. Nature 446, 185–189 (2007).

    CAS  PubMed  Google Scholar 

  93. 93

    Doupé, D. P., Klein, A. M., Simons, B. D. & Jones, P. H. The ordered architecture of murine ear epidermis is maintained by progenitor cells with random fate. Dev. Cell 18, 317–323 (2010).

    PubMed  Google Scholar 

  94. 94

    Lopez-Garcia, C., Klein, A. M., Simons, B. D. & Winton, D. J. Intestinal stem cell replacement follows a pattern of neutral drift. Science 330, 822–825 (2010).

    CAS  PubMed  Google Scholar 

  95. 95

    Snippert, H. J. et al. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134–144 (2010).

    CAS  PubMed  Google Scholar 

  96. 96

    Klein, A. M., Nakagawa, T., Ichikawa, R., Yoshida, S. & Simons, B. D. Mouse germ line stem cells undergo rapid and stochastic turnover. Cell Stem Cell 7, 214–224 (2010).

    CAS  PubMed  Google Scholar 

  97. 97

    Klein, A. M. & Simons, B. D. Universal patterns of stem cell fate in cycling adult tissues. Development 138, 3103–3111 (2011).

    CAS  PubMed  Google Scholar 

  98. 98

    Hamant, O. et al. Developmental patterning by mechanical signals in Arabidopsis. Science 322, 1650–1655 (2008).

    CAS  PubMed  Google Scholar 

  99. 99

    Heisler, M. G. et al. Alignment between PIN1 polarity and microtubule orientation in the shoot apical meristem reveals a tight coupling between morphogenesis and auxin transport. PLoS Biol. 8, e1000516 (2010).

    PubMed  PubMed Central  Google Scholar 

  100. 100

    Gerisch, G. Zellfunktionen und Zellfunktionswechsel in der Entwicklung von Dictyostelium discoideum. Exp. Cell Res. 25, 535–554 (1961).

    CAS  PubMed  Google Scholar 

  101. 101

    Glazier, J. A. & Graner, F. Simulation of the differential adhesion driven rearrangement of biological cells. Phys. Rev. E Stat. Phys. Plasmas Fluids Relat. Interdiscip. Topics 47, 2128–2154 (1993).

    CAS  PubMed  Google Scholar 

  102. 102

    Savill, N. J. & Hogeweg, P. Modelling morphogenesis: from single cells to crawling slugs. J. Theor. Biol. 184, 229–235 (1997).

    Google Scholar 

  103. 103

    Maree, A. F. M. & Hogeweg, P. How amoeboids self-organize into a fruiting body: multicellular coordination in Dictyostelium discoideum. Proc. Natl Acad. Sci. USA 98, 3879–3883 (2001).

    CAS  PubMed  Google Scholar 

  104. 104

    Sawai, S., Thomason, P. A. & Cox, E. C. An autoregulatory circuit for long-range self-organization in Dictyostelium cell populations. Nature 433, 323–326 (2005).

    CAS  PubMed  Google Scholar 

  105. 105

    Hayashi, T. & Carthew, R. W. Surface mechanics mediate pattern formation in the developing retina. Nature 431, 647–652 (2004).

    CAS  PubMed  Google Scholar 

Download references


The authors would like to thank A. Aulehla, M. Heisler, W. Huber, B. D. Simons and the members of the Hiiragi laboratory for critical reading of the manuscript and helpful discussion. They apologize to colleagues whose work could not be cited owing to space limitations. Work in the Hiiragi laboratory has been supported by the Max Planck Society, European Research Council under the European Community's Seventh Framework Programme (EU-FP7), Stem Cell Network North Rhine Westphalia, German Research Foundation (DFG) and the World Premier International Research Center Initiative (WPI), Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. Work in the Nédélec laboratory has been supported by EU-FP7 network Systems Microscopy (grant 258068) and EU-FP7 project MitoSys (grant 241548).

Author information



Corresponding author

Correspondence to Takashi Hiiragi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links


Takashi Hiiragi's homepage

PowerPoint slides

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wennekamp, S., Mesecke, S., Nédélec, F. et al. A self-organization framework for symmetry breaking in the mammalian embryo. Nat Rev Mol Cell Biol 14, 452–459 (2013). https://doi.org/10.1038/nrm3602

Download citation

Further reading