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Sequential formation and resolution of multiple rosettes drive embryo remodelling after implantation

Nature Cell Biology volume 20, pages 1278–1289 (2018)Cite this article

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Abstract

The morphogenetic remodelling of embryo architecture after implantation culminates in pro-amniotic cavity formation. Despite its key importance, how this transformation occurs remains unknown. Here, we apply high-resolution imaging of embryos developing in vivo and in vitro, spatial RNA sequencing and 3D trophoblast stem cell models to determine the sequence and mechanisms of these remodelling events. We show that cavitation of the embryonic tissue is followed by folding of extra-embryonic tissue to mediate the formation of a second extra-embryonic cavity. Concomitantly, at the boundary between embryonic and extra-embryonic tissues, a hybrid 3D rosette forms. Resolution of this rosette enables the embryonic cavity to invade the extra-embryonic tissue. Subsequently, β1-integrin signalling mediates the formation of multiple extra-embryonic 3D rosettes. Podocalyxin exocytosis leads to their polarized resolution, permitting the extension of embryonic and extra-embryonic cavities and their fusion into a unified pro-amniotic cavity. These morphogenetic transformations of embryogenesis reveal a previously unappreciated mechanism for lumen expansion and fusion.

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Fig. 1: Remodelling of embryo architecture and pro-amniotic cavity formation.
Fig. 2: ECM–β1-integrin signalling is essential for extra-embryonic ectoderm polarization and morphogenesis.
Fig. 3: ECM-dependent 3D rosette formation throughout the extra-embryonic ectoderm.
Fig. 4: Epiblast–extra-embryonic ectoderm hybrid rosette polarized resolution drives epiblast reorganization.
Fig. 5: Rosette formation/resolution-mediated pro-amniotic cavity formation.
Fig. 6: Spatial transcriptome analysis of pro-amniotic cavity formation.
Fig. 7: Polarized pattern of podocalyxin exocytosis during rosette resolution and cavities expansion.
Fig. 8: Cell intercalation during the final step of pro-amniotic cavity formation.

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Data availability

RNA-seq data that support the findings of this study have been deposited in the Gene Expression Omnibus (GEO) under accession code GSE110808. Source data for Figs. 1b, 2c,e,g,i,j,l and 3c,h and Supplementary Fig. 3c,d have been provided as Supplementary Table 2. Source data for Fig. 1g,h, 3e,f, 4d,f and 5c,d and Supplementary Fig. 3c are provided as Supplementary Videos. All other data supporting the findings of this study are available from the corresponding author on reasonable request.

Change history

  • 19 November 2018

    In the version of this Article originally published, the first name of author Guangdun Peng was spelled incorrectly as Guangdum. This has now been amended in all versions of the Article.

References

  1. Ang, S. L. & Constam, D. B. A gene network establishing polarity in the early mouse embryo. Semin. Cell Dev. Biol. 15, 555–561 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Kojima, Y., Tam, O. H. & Tam, P. P. Timing of developmental events in the early mouse embryo. Semin. Cell Dev. Biol. 34, 65–75 (2014).

    Article  CAS  PubMed  Google Scholar 

  3. Arnold, S. J. & Robertson, E. J. Making a commitment: cell lineage allocation and axis patterning in the early mouse embryo. Nat. Rev. Mol. Cell Biol. 10, 91–103 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Rossant, J. & Tam, P. P. New insights into early human development: lessons for stem cell derivation and differentiation. Cell Stem Cell 20, 18–28 (2017).

    Article  CAS  PubMed  Google Scholar 

  5. Bedzhov, I. & Zernicka-Goetz, M. Self-organizing properties of mouse pluripotent cells initiate morphogenesis upon implantation. Cell 156, 1032–1044 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Shahbazi, M. N. et al. Pluripotent state transitions coordinate morphogenesis in mouse and human embryos. Nature 552, 239–243 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lee, J. L. & Streuli, C. H. Integrins and epithelial cell polarity. J. Cell Sci. 127, 3217–3225 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Barczyk, M., Carracedo, S. & Gullberg, D. Integrins. Cell Tissue Res. 339, 269–280 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Hiramatsu, R. et al. External mechanical cues trigger the establishment of the anterior–posterior axis in early mouse embryos. Dev. Cell 27, 131–144 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Shih, H. P., Panlasigui, D., Cirulli, V. & Sander, M. ECM signalling regulates collective cellular dynamics to control pancreas branching morphogenesis. Cell Rep. 14, 169–179 (2016).

    Article  CAS  PubMed  Google Scholar 

  11. Stephens, L. E. et al. Deletion of β1 integrins in mice results in inner cell mass failure and peri-implantation lethality. Genes Dev. 9, 1883–1895 (1995).

    Article  CAS  PubMed  Google Scholar 

  12. Sakai, T., Larsen, M. & Yamada, K. M. Fibronectin requirement in branching morphogenesis. Nature 423, 876–881 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Blankenship, J. T., Backovic, S. T., Sanny, J. S., Weitz, O. & Zallen, J. A. Multicellular rosette formation links planar cell polarity to tissue morphogenesis. Dev. Cell 11, 459–470 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Trichas, G. et al. Multi-cellular rosettes in the mouse visceral endoderm facilitate the ordered migration of anterior visceral endoderm cells. PLoS Biol. 10, e1001256 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Harding, M. J., McGraw, H. F. & Nechiporuk, A. The roles and regulation of multicellular rosette structures during morphogenesis. Development 141, 2549–2558 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bryant, D. M. et al. A molecular network for de novo generation of the apical surface and lumen. Nat. Cell Biol. 12, 1035–1045 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Riedl, J. et al. LifeAct mice for studying F-actin dynamics. Nat. Methods 7, 168–169 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Muzumdar, M. D., Tasic, B., Miyamichi, K., Li, L. & Luo, L. A global double-fluorescent Cre reporter mouse. Genesis 45, 593–605 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Peng, G. et al. Spatial transcriptome for the molecular annotation of lineage fates and cell identity in mid-gastrula mouse embryo. Dev. Cell 36, 681–697 (2016).

    Article  CAS  PubMed  Google Scholar 

  20. Rivera-Perez, J. A. & Magnuson, T. Primitive streak formation in mice is preceded by localized activation of Brachyury and Wnt3. Dev. Biol. 288, 363–371 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Jung, J. J. et al. Syntaxin 16 regulates lumen formation during epithelial morphogenesis. PLoS ONE 8, e61857 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Willenborg, C. et al. Interaction between FIP5 and SNX18 regulates epithelial lumen formation. J. Cell Biol. 195, 71–86 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mrozowska, P. S. & Fukuda, M. Regulation of podocalyxin trafficking by Rab small GTPases in 2D and 3D epithelial cell cultures. J. Cell Biol. 213, 355–369 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Takeda, T., Go, W. Y., Orlando, R. A. & Farquhar, M. G. Expression of podocalyxin inhibits cell–cell adhesion and modifies junctional properties in Madin-Darby canine kidney cells. Mol. Biol. Cell 11, 3219–3232 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hoijman, E., Rubbini, D., Colombelli, J. & Alsina, B. Mitotic cell rounding and epithelial thinning regulate lumen growth and shape. Nat. Commun. 6, 7355 (2015).

    Article  CAS  PubMed  Google Scholar 

  26. Kesavan, G. et al. Cdc42-mediated tubulogenesis controls cell specification. Cell 139, 791–801 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Portereiko, M. F. & Mango, S. E. Early morphogenesis of the Caenorhabditis elegans pharynx. Dev. Biol. 233, 482–494 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Villasenor, A., Chong, D. C., Henkemeyer, M. & Cleaver, O. Epithelial dynamics of pancreatic branching morphogenesis. Development 137, 4295–4305 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yang, Z. et al. De novo lumen formation and elongation in the developing nephron: a central role for afadin in apical polarity. Development 140, 1774–1784 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kao, R. M., Vasilyev, A., Miyawaki, A., Drummond, I. A. & McMahon, A. P. Invasion of distal nephron precursors associates with tubular interconnection during nephrogenesis. J. Am. Soc. Nephrol. 23, 1682–1690 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bedzhov, I., Leung, C. Y., Bialecka, M. & Zernicka-Goetz, M. In vitro culture of mouse blastocysts beyond the implantation stages. Nat. Protoc. 9, 2732–2739 (2014).

    Article  CAS  PubMed  Google Scholar 

  32. Ohinata, Y. & Tsukiyama, T. Establishment of trophoblast stem cells under defined culture conditions in mice. PLoS ONE 9, e107308 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Chen, J. et al. Spatial transcriptomic analysis of cryosectioned tissue samples with Geo-seq. Nat. Protoc. 12, 566–580 (2017).

    Article  CAS  PubMed  Google Scholar 

  34. Trapnell, C., Pachter, L. & Salzberg, S. L. TopHat: discovering splice junctions with RNA-seq. Bioinformatics 25, 1105–1111 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Kim, D. et al. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 14, R36 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Hong, F. et al. RankProd: a bioconductor package for detecting differentially expressed genes in meta-analysis. Bioinformatics 22, 2825–2827 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Huang da, W., Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44–57 (2009).

    Article  PubMed  Google Scholar 

  38. Johnson, W. E., Li, C. & Rabinovic, A. Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 8, 118–127 (2007).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to D. Glover, F. Antonica, M. Shahbazi, G. Amadei and S. Harrison for feedback on the manuscript. We also thanks J. Nichols for the Confetti TSCs, I. Roswell (Francis Crick Institute) for LifeAct-GFP mice and K. O’Holleran (Cambridge Advanced Imaging Center) for help with the laser ablation experiments. The M.Z.-G. lab is supported by grants from the European Research Council (669198) and the Welcome Trust (098287/Z/12/Z), and the EU Horizon 2020 Marie Sklodowska-Curie actions (ImageInLife, 721537). C.K. is supported by the BBSRC Doctoral training studentship.

Author information

Author notes

  1. These authors contributed equally: Neophytos Christodoulou, Christos Kyprianou.

Authors and Affiliations

  1. Mammalian Embryo and Stem Cell Group, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK

    Neophytos Christodoulou, Christos Kyprianou, Antonia Weberling & Magdalena Zernicka-Goetz

  2. State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China

    Ran Wang, Guizhong Cui, Guangdun Peng & Naihe Jing

  3. School of Life Science and Technology, ShanghaiTech University, Shanghai, China

    Naihe Jing

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  1. Neophytos Christodoulou
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Contributions

N.C. and C.K. designed and carried out the experiments and data analysis. A.W. contributed to embryo live imaging. G.C. and G.P. performed the embryo cryosection, laser microdissection and library construction experiments for RNA-seq. R.W. carried out the RNA-seq analysis. N.J. supervised the work related to spatial trancriptome analysis. M.Z.-G. conceived and supervised the study and wrote the manuscript with the help of N.C. and C.K.

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Correspondence to Magdalena Zernicka-Goetz.

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Integrated supplementary information

Supplementary Figure 1 Analysis of extra-embryonic ectoderm tissue folding in embryos derived after decidua fixation.

(a) Experimental strategy for post-fixation embryo recovery. (b) Representative E5.0 recovered from a fixed decidua. Accumulation of actin and phosphorylated myosin (arrows) is evident at the proximal tip of extra-embryonic ectoderm cells in recovered embryos post-fixation. This indicates that apical actin accumulation and apical constriction tissue folding (see Fig. 1) is an active morphogenetic process and not a wound healing response stemming from the recovery of embryos from deciduae. (c) 3 representative examples of E5.0 embryos recovered from fixed deciduae. Arrows indicate actin apical accumulation at extra-embryonic ectoderm most proximal cells. Image represents 3 biological replicates. Scale bars= 20 um.

Supplementary Figure 2 ECM/ β1-integrin during extra-embryonic ectoderm and TSCs polarization.

(a) ECM/ β1-integrin localization in E5.5 embryo revealed by antibodies for laminin, β1-integrin and active β1-integrin (9EG7). Image representative of 10 embryos (b) Representative examples of TSC clumps culture in suspension in the presence or absence of Matrigel. In the absence of Matrigel TSCs fail to polarize. Specifically the cells fail to acquire columnar morphology (indicated by F-actin staining) and they don’t display apical Golgi polarization (GM130 staining; arrowheads) compared with TSCs cultured in the presence of Matrigel. Image representative of 3 biological replicates (c) The effect of collagenase IV (COLIV) treatment on the surrounding basement membrane (assessed by laminin, collagen and perlecan staining) of E5.5 embryos cultured for 5h in the presence or absence of COLIV. Image representative of 5 biological replicates (d) β1-integrin activation status (indicated by 9EG7 antibody staining) in control and COLIV treated embryos. White arrowheads indicate basal site of ExE outside cells. Image representative of 2 biological replicates (e) The effect of COLIV treatment on the localization of the tight junction’s localisation assessed by ZO-1 staining in E5.5 embryos (two different z slices in control embryo; Z1 and Z2). Arrows point to apical site while arrowheads point towards the basal site. Image representative of 10 embryos (f) β1-integrin activation status (indicated by 9EG7 antibody staining) in control and β1-integrin blocking antibody (Ha2/5) treated TSCs in 3D culture; Image representative of 2 biological replicates. Scale bars=20um.

Supplementary Figure 3 Characterization of extra-embryonic ectoderm cells.

(a) Images of different Z slices (0.8 um) from a representative E5.5 (Stage III) embryo. Extra-embryonic ectoderm (ExE) rosettes are outlined with a dashed line. Arrows denote rosettes’ centre. Image representative of 20 embryos (b) Representative example of an ExE rosette (dashed outline) found in E5.5 embryo as revealed by cell morphology (E-cadherin) and polarization (ZO-1). Orthogonal views (XZ, YZ) of the embryo are displayed on the right and the bottom of the image with the segmented rosette as viewed in the respective orthoslice. Image representative of 20 embryos. (c) Cell aspect ratio comparison of outside, inside vs inside cells that contribute to rosettes (Inside cells, R). Two sided unpaired student t-test;****p<0.0001;mean± SEM; n=50 inside cells and n=47 inside rosette cells. (d) Plot of long and short axis. Two separate clusters are indicated (magenta and grey outlines). Cluster shown with magenta consists of outside cells and inside cells contributing to rosettes (inside cells R). Cluster shown with grey consists of inside cells that do not contribute to rosettes. Blue dashed line: y=x. n=50 outside and inside cells and n=47 inside rosette cells. Scale bars=20um.

Supplementary Figure 4 Epiblast remodelling upon hybrid rosette resolution.

Stills from a time lapse movie of a LifeAct-GFP embryo showing epiblast EPI remodelling after hybrid rosette resolution. Cells are arbitrarily colour-coded for tracking. EPI: purple, yellow and cyan cells; ExE: blue, red and green cells. Image representative of 3 embryos. Scale bar=20um.

Supplementary Figure 5 Extra-embryonic ectoderm rosettes facilitate cavities extension and fusion.

(a) Representative example of E5.5 (stage III) embryo stained for E-Cadherin. White dots label the cells contributing to the epiblast (EPI) cavity’s proximal rosette (adjacent to EPI-ExE boundary). Image representative of 15 embryos. (b) Example of a resolving EPI cavity’s proximal rosette (dots show cells contributing to the rosette) through loss of cell-cell contacts (cells marked with hollow dots) of ExE cells at the boundary. YZ projection is displayed on the right of the image. Image representative of 10 embryos (c) Stills from a time lapse movie of an E5.5 LifeAct-GFP embryo showing EPI cavity expansion after EPI cavity’s proximal rosette resolution. Cells are arbitrarily color-coded for tracking. Image representative of 3 embryos (d)E5.5 (stage III) embryo stained for E-Cadherin and tight junction protein ZO-1. Two different z slices are presented (Z0 and Z17, Z step=0.8 um) one showing the ExE cavity and the other the overlaying rosette (white dots). YZ projection of rosette (white dots showing cells contributing to rosette) and ExE cavities shown on the far right of the panel. *=ExE cavity, **=EPI cavity. Image representative of 10 embryos. (e) Representative example of ExE cavity (asterisk in YZ projections, right panel) connected with the centre of an ExE cavity proximal rosette (arrowhead points to the centre of this rosette; magenta dots indicate cells contributing to both rosette and ExE cavity where white dots indicate the rest of rosette’s cells) through a tract of ZO-1 (arrow). White dotted line = EPI-ExE boundary. *=ExE cavity, **=EPI cavity. Image representative of 10 embryos. (f) Two representative examples of an invading EPI cavity and an extended ExE cavity connected with a polarized tract of ZO-1 (white circle). Image representative of 6 embryos. Scale bars = 20um.

Supplementary Figure 6 Spatial transcriptome analysis of E5.25-E5.75 embryos.

(a) Principal component analysis (PCA) of sections along the proximo-distal embryo axis from at E5.25, E5.5 and E5.75. Yellow outline: VE, Purple outline: epiblast (EPI), Cyan outline: extra-embryonic ectoderm (ExE). (b) Gene expression pattern for EPI (Pou5f1) and ExE (CDX2) markers from E5.25-E5.75. (c) Gene expression pattern for Wnt3 and T from E5.25-E5.75. (d) Differential gene expression analysis heat maps for GO term: integrin mediated signalling. E5.25: sections 2-4 EPI, sections 6-8 ExE ; E5.5: sections 2,4,5 EPI, sections 6-11 ExE.

Supplementary Figure 7 Differential gene expression analysis of embryonic and extra-embryonic compartments.

(a)Differential gene expression analysis heat maps between epiblast (EPI) and extra-embryonic ectoderm (ExE) in E5.25, E5.5 and E5.75 embryos. Representative gene ontology (G0) terms enriched in each tissue are shown on the right of each heat map. E5.25: sections 2-4 EPI, sections 6-8 ExE; E5.5: sections 2,4,5 EPI, sections 6-11 ExE; E5.75 sections 3-8 EPI, sections 9-19 ExE. n=1 E5.25, n=1 E5.5 and n=1 E5.75 embryos (b) Combined principal component analysis (PCA) for embryonic and extra-embryonic sections from E5.25-E5.75. Purple outline: E5.25-E5.5 EPI; Cyan outline: E5.25-E5.5 ExE; Dashed purple outline: E5.75 EPI; Dashed cyan outline: E5.75 ExE. n=1 E5.25, n=1 E5.5 and n=1 E5.75 embryos.

Supplementary Figure 8 Cell intercalation after initial cavities fusion results in the formation of a pseudostratified epithelium.

(a)ExE acquires a pseudostratified epithelium morphology shortly after unification of the cavities. Image representative of 10 embryos. (b)After cavities fusion ExE cells show intercalative behaviour (green and yellow asterisks). Image representative of 5 embryos. (c) 3 different optical Z slices (0.6um) of a representative example of an E5.75(stage IV) embryo. Dashed outline in left panel shows pro-amniotic cavity spanning through EPI and ExE. In different Z slices (middle and right panel) ExE cells intercalating towards the basement membrane can be identified. Polarized pMLC localization displays the polarized nature of this event. Insets in middle and right panel show magnified fluorescent intensity color coded images of ExE intercalating cells. Image representative of 5 embryos. Scale bars=20um.

Supplementary information

Supplementary Information

Supplementary Figures 1–8, Supplementary Table and Supplementary Movie legends.

Reporting Summary

Supplementary Table 1

Processed RNA-seq data.

Supplementary Table 2

Statistics source data.

Supplementary Video 1

Tissue-folding-mediated extra-embryonic cavity formation.

Supplementary Video 2

Tissue-folding-mediated extra-embryonic cavity formation in 3D.

Supplementary Video 3

Apical constriction during extra-embryonic ectoderm tissue folding.

Supplementary Video 4

3D segmentation of representative extra-embryonic ectoderm rosettes.

Supplementary Video 5

3D segmentation of neighbouring extra-embryonic ectoderm rosettes.

Supplementary Video 6

Hybrid rosette resolution precedes epiblast remodelling (1).

Supplementary Video 7

Hybrid rosette resolution precedes epiblast remodelling (2).

Supplementary Video 8

Laser ablation mediated hybrid rosette resolution.

Supplementary Video 9

Polarized tract connects the centre of a rosette with the embryonic cavity.

Supplementary Video 10

ExE rosettes facilitate epiblast cavity extension (1).

Supplementary Video 11

ExE rosettes facilitate epiblast cavity extension (2).

Supplementary Video 12

ExE rosettes facilitate extra-embryonic cavity extension.

Supplementary Video 13

Rosette-mediated embryonic and extra-embryonic cavities extension.

Supplementary Video 14

Extra-embryonic ectoderm cell intercalation upon initial cavities fusion.

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Christodoulou, N., Kyprianou, C., Weberling, A. et al. Sequential formation and resolution of multiple rosettes drive embryo remodelling after implantation. Nat Cell Biol 20, 1278–1289 (2018). https://doi.org/10.1038/s41556-018-0211-3

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