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.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Reproductive Biology and Endocrinology Open Access 09 December 2021
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Rossant, J. & Tam, P. P. L. Emerging asymmetry and embryonic patterning in early mouse development. Dev. Cell 7, 155–164 (2004).
Rossant, J. & Tam, P. P. L. Blastocyst lineage formation, early embryonic asymmetries and axis patterning in the mouse. Development 136, 701–713 (2009).
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).
Johnson, M. H. & Ziomek, C. A. The foundation of two distinct cell lineages within the mouse morula. Cell 24, 71–80 (1981).
Graham, C. F. & Lehtonen, E. Formation and consequences of cell patterns in preimplantation mouse development. J. Embryol. Exp. Morphol. 49, 277–294 (1979).
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).
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).
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).
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).
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).
Rossant, J. & Lis, W. T. Potential of isolated mouse inner cell masses to form trophectoderm derivatives in vivo. Dev. Biol. 70, 255–261 (1979).
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).
Driever, W. & Nüsslein-Volhard, C. A gradient of bicoid protein in Drosophila embryos. Cell 54, 83–93 (1988).
Driever, W. & Nüsslein-Volhard, C. The bicoid protein determines position in the Drosophila embryo in a concentration-dependent manner. Cell 54, 95–104 (1988).
Goldstein, B. & Hird, S. N. Specification of the anteroposterior axis in Caenorhabditis elegans. Development 122, 1467–1474 (1996).
Speman, H. Embryonic development and induction. Am. J. Med. Sci. 196, 738 (1938).
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).
Dalcq, A. Introduction to General Embryology (Oxford Univ. Press, 1957).
Piotrowska, K. & Zernicka-Goetz, M. Role for sperm in spatial patterning of the early mouse embryo. Nature 409, 517–521 (2001).
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).
Gardner, R. Specification of embryonic axes begins before cleavage in normal mouse development. Development 128, 839–847 (2001).
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).
Gardner, R. Experimental analysis of second cleavage in the mouse. Hum. Reprod. 17, 3178–3189 (2002).
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).
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).
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).
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).
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).
Marikawa, Y. & Alarcon, V. B. Establishment of trophectoderm and inner cell mass lineages in the mouse embryo. Mol. Reprod. Dev. 76, 1019–1032 (2009).
Tarkowski, A. K. Experiments on the development of isolated blastomers of mouse eggs. Nature 184, 1286–1287 (1959).
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).
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).
Dietrich, J. E. & Hiiragi, T. Stochastic patterning in the mouse pre-implantation embryo. Development 134, 4219–4231 (2007).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Yamanaka, Y., Lanner, F. & Rossant, J. FGF signal-dependent segregation of primitive endoderm and epiblast in the mouse blastocyst. Development 137, 715–724 (2010).
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).
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).
Dietrich, J. E. & Hiiragi, T. Stochastic processes during mouse blastocyst patterning. Cells Tissues Organs 188, 46–51 (2008).
Chambers, I. et al. Nanog safeguards pluripotency and mediates germline development. Nature 450, 1230–1234 (2007).
Kalmar, T. et al. Regulated fluctuations in Nanog expression mediate cell fate decisions in embryonic stem cells. PLoS Biol. 7, e1000149 (2009).
Silva, J. & Smith, A. Capturing pluripotency. Cell 132, 532–536 (2008).
Kurimoto, K. et al. An improved single-cell cDNA amplification method for efficient high-density oligonucleotide microarray analysis. Nucleic Acids Res. 34, e42 (2006).
Tang, F. et al. mRNA-seq whole-transcriptome analysis of a single cell. Nature Methods 6, 377–382 (2009).
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).
Tang, F. et al. Deterministic and stochastic allele specific gene expression in single mouse blastomeres. PLoS ONE 6, e21208 (2011).
Itzkovitz, S., Blat, I. C., Jacks, T., Clevers, H. & van Oudenaarden, A. Optimality in the development of intestinal crypts. Cell 148, 608–619 (2012).
Itzkovitz, S. et al. Single-molecule transcript counting of stem-cell markers in the mouse intestine. Nature Cell Biol. 14, 106–114 (2011).
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).
Raj, A., Rifkin, S. A., Andersen, E. & van Oudenaarden, A. Variability in gene expression underlies incomplete penetrance. Nature 463, 913–918 (2010).
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).
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).
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).
Johnson, M. H. From mouse egg to mouse embryo: polarities, axes, and tissues. Annu. Rev. Cell Dev. Biol. 25, 483–512 (2009).
Wennekamp, S. & Hiiragi, T. Stochastic processes in the development of pluripotency in vivo. Biotechnol. J. 7, 737–744 (2012).
Müller, P. et al. Differential diffusivity of Nodal and Lefty underlies a reaction–diffusion patterning system. Science 336, 721–724 (2012).
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).
Niwa, H. et al. Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation. Cell 123, 917–929 (2005).
Honda, H., Motosugi, N., Nagai, T., Tanemura, M. & Hiiragi, T. Computer simulation of emerging asymmetry in the mouse blastocyst. Development 135, 1407–1414 (2008).
To, T. L. & Maheshri, N. Noise can induce bimodality in positive transcriptional feedback loops without bistability. Science 327, 1142–1145 (2010).
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).
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).
McDole, K. & Zheng, Y. Generation and live imaging of an endogenous Cdx2 reporter mouse line. Genesis 50, 775–782 (2012).
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).
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).
Camazine, S. et al. Self-Organization in Biological Systems (Princeton Univ. Press, 2003).
Krupinski, P., Chickarmane, V. & Peterson, C. Simulating the mammalian blastocyst — molecular and mechanical interactions pattern the embryo. PLoS Comput. Biol. 7, e1001128 (2011).
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).
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).
Nishioka, N. et al. Tead4 is required for specification of trophectoderm in pre-implantation mouse embryos. Mech. Dev. 125, 270–283 (2008).
Yagi, R. et al. Transcription factor TEAD4 specifies the trophectoderm lineage at the beginning of mammalian development. Development 134, 3827–3836 (2007).
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).
Avilion, A. A. et al. Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev. 17, 126–140 (2003).
Chambers, I. et al. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113, 643–655 (2003).
Mitsui, K. et al. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113, 631–642 (2003).
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).
Tarkowski, A. K. Mouse chimaeras developed from fused eggs. Nature 190, 857–860 (1961).
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).
Gärtner, K. & Baunack, E. Is the similarity of monozygotic twins due to genetic factors alone? Nature 292, 646–647 (1981).
Gardner, R. L. Mouse chimeras obtained by the injection of cells into the blastocyst. Nature 220, 596–597 (1968).
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).
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).
Karsenti, E. Self-organization in cell biology: a brief history. Nature Rev. Mol. Cell Biol. 9, 255–262 (2008).
Sasai, Y. Cytosystems dynamics in self-organization of tissue architecture. Nature 493, 318–326 (2013).
Clayton, E. et al. A single type of progenitor cell maintains normal epidermis. Nature 446, 185–189 (2007).
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).
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).
Snippert, H. J. et al. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134–144 (2010).
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).
Klein, A. M. & Simons, B. D. Universal patterns of stem cell fate in cycling adult tissues. Development 138, 3103–3111 (2011).
Hamant, O. et al. Developmental patterning by mechanical signals in Arabidopsis. Science 322, 1650–1655 (2008).
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).
Gerisch, G. Zellfunktionen und Zellfunktionswechsel in der Entwicklung von Dictyostelium discoideum. Exp. Cell Res. 25, 535–554 (1961).
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).
Savill, N. J. & Hogeweg, P. Modelling morphogenesis: from single cells to crawling slugs. J. Theor. Biol. 184, 229–235 (1997).
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).
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).
Hayashi, T. & Carthew, R. W. Surface mechanics mediate pattern formation in the developing retina. Nature 431, 647–652 (2004).
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).
The authors declare no competing financial interests.
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
This article is cited by
Nature Reviews Molecular Cell Biology (2023)
Reproductive Biology and Endocrinology (2021)
Nature Materials (2021)
Cellular and Molecular Life Sciences (2020)