Molecular characterisation of the establishment of and exit from pluripotency in the mouse embryo by combining live-imaging and single-cell RNA-seq

• Applicant: Dr. Takashi Hiiragi
• Subject Area: Reproductive Medicine, Urology ; Developmental Biology
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 266274777

• Final Report Year: 2019

Final Report Abstract

Understanding of the mechanism for establishing pluripotent cells in the early mammalian embryo is fundamental to developmental biology, stem cell biology and regenerative medicine. The aim of this project was to understand the molecular mechanism of symmetry breaking in the early mouse embryo leading to this first cell fate segregation and how the first embryo pattern is robustly established despite the variabilities in the processes. As we have found that gene expression variabilities do not predict or impact on cell fate specification, we developed an experimental framework integrating biology, physics and mathematics to consider not only chemical (genes) but also mechanical factors in development. We discovered that difference in cell contact provides positional information for outside cells and directs the apical polarization that is in turn required and sufficient for the first cell fate specification. We have further identified that the asymmetric segregation of the apical domain generates cells with different contractility, which triggers their sorting into inner and outer positions within the embryo. Together, we proposed a model in which coupling between molecular, cellular and physical signals across the scales drives multi-cellular self-organisation and robust patterning in the early mammalian embryo. This model of self-organisation may be widely applicable to formation and regeneration of various tissues.

Publications

• Inverted light-sheet microscope for imaging mouse pre-implantation development. Nature Methods (2016) 13, 139-142
  Strnad, Petr; Gunther, Stefan; Reichmann, Judith; Krzic, Uros; Balazs, Balint; de Medeiros, Gustavo; Norlin, Nils; Hiiragi, Takashi; Hufnagel, Lars & Ellenberg, Jan
  
• Pulsatile cellautonomous contractility drives compaction in the mouse embryo. Nat Cell Biol (2015) 17, 849–855
  Maître, Jean-Léon; Niwayama, Ritsuya; Turlier, Hervé; Nédélec, François & Hiiragi, Takashi
  
• Venus trap in the mouse embryo reveals distinct molecular dynamics underlying specification of first embryonic lineages. EMBO reports (2015) 16(8), 1005-1021
  Dietrich, Jens‐Erik; Panavaite, Laura; Gunther, Stefan; Wennekamp, Sebastian; Groner, Anna C; Pigge, Anton; Salvenmoser, Stefanie; Trono, Didier; Hufnagel, Lars & Hiiragi, Takashi
  
• Asymmetric division of contractile domains couples cell positioning and fate specification. Nature (2016) 536(7616), 344–348
  Maître, Jean-Léon; Turlier, Hervé; Illukkumbura, Rukshala; Eismann, Björn; Niwayama, Ritsuya; Nédélec, François & Hiiragi, Takashi
  
• Inferring cellular forces from image stacks. Philos Trans R Soc Lond, B, Biol Sci (2017) 372(1720), 20160261
  Veldhuis, Jim H.; Ehsandar, Ahmad; Maître, Jean-Léon; Hiiragi, Takashi; Cox, Simon & Brodland, G. Wayne
  
• The Apical Domain Is Required and Sufficient for the First Lineage Segregation in the Mouse Embryo. Developmental Cell (2017) 40(3), 235–247.e7
  Korotkevich, Ekaterina; Niwayama, Ritsuya; Courtois, Aurélien; Friese, Stefanie; Berger, Nicolas; Buchholz, Frank & Hiiragi, Takashi
  
• Dual-spindle formation in zygotes keeps parental genomes apart in early mammalian embryos. Science (2018) 361, 189-193
  Reichmann, Judith; Nijmeijer, Bianca; Hossain, M. Julius; Eguren, Manuel; Schneider, Isabell; Politi, Antonio Z.; Roberti, M. Julia; Hufnagel, Lars; Hiiragi, Takashi & Ellenberg, Jan
  
• Hydraulic control of embryo size, tissue shape and cell fate
  Chan, Chii Jou; Costanzo, Maria; Ruiz-Herrero, Teresa; Mönke, Gregor; Petrie, Ryan J.; Mahadevan, L. & Hiiragi, Takashi