Molekulare Charakterisierung der Etablierung der Pluripotenz im Mausembryo und der Verlust dieses Zustandes durch die Kombination von Live-Imaging und Einzelzell-RNA Sequenzierung

• Antragsteller: Dr. Takashi Hiiragi
• Fachliche Zuordnung: Reproduktionsmedizin, Urologie ; Entwicklungsbiologie
• Förderung: Förderung von 2015 bis 2018
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 266274777

• Erstellungsjahr: 2019

Zusammenfassung der Projektergebnisse

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.

Projektbezogene Publikationen (Auswahl)

• Hydraulic control of embryo size, tissue shape and cell fate
  Chan, C.J., Costanzo, M., Ruiz-Herrero, T., Mönke, G., Ryan, P., Mahadevan, L. and Hiiragi, T.
  
• Pulsatile cellautonomous contractility drives compaction in the mouse embryo. Nat Cell Biol (2015) 17, 849–855
  Maître, J.-L., Niwayama, R., Turlier, H., Nédélec, F. and Hiiragi, T.
  
• Venus trap in the mouse embryo reveals distinct molecular dynamics underlying specification of first embryonic lineages. EMBO reports (2015) 16(8), 1005-1021
  Dietrich, J.-E., Panavaite, L., Gunther, S., Wennekamp, S., Groner, A.C., Pigge, A., Salvenmoser, S., Trono, D., Hufnagel, L. and Hiiragi, T.
  
• Asymmetric division of contractile domains couples cell positioning and fate specification. Nature (2016) 536(7616), 344–348
  Maître, J.-L., Turlier, H., Illukkumbura, R., Eismann, B., Niwayama, R., Nedelec, F. and Hiiragi, T.
  
• Inverted light-sheet microscope for imaging mouse pre-implantation development. Nature Methods (2016) 13, 139-142
  Strnad, P., Gunther, S., Reichmann, J., Krzic, U., Balazs, B., de Medeiros, G., Norlin, N., Hiiragi, T., Hufnagel, L. and Ellenberg, J.
  
• Inferring cellular forces from image stacks. Philos Trans R Soc Lond, B, Biol Sci (2017) 372(1720), 20160261
  Veldhuis, J.H., Ehsandar, A., Maître, J.-L., Hiiragi, T., Cox, S. and Brodland, G. W.
  
• 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, E., Niwayama, R., Courtois, A., Friese, S., Berger, N., Buchholz, F. and Hiiragi, T.
  
• Dual-spindle formation in zygotes keeps parental genomes apart in early mammalian embryos. Science (2018) 361, 189-193
  Reichmann, J., Nijmeijer, B., Hussain, M.J., Eguren, M., Schneider, I., Politi, A.Z., Roberti, M.J., Hufnagel, L, Hiiragi, T. and Ellenberg, J.