From blastocyst to egg cylinder: analysis of peri-implantation embryogenesis

• Applicant: Dr. Ivan Bedzhov
• Subject Area: Developmental Biology
• Term: from 2015 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 278835329

• Final Report Year: 2023

Final Report Abstract

The fusion of gametes triggers a chain reaction of developmental events, transforming the fertilized egg into a new organism. Two subsequent cell fate decisions set up the embryonic (epiblast) and the extraembryonic (trophectoderm and primitive endoderm) lineages during the embryo’s journey from the oviduct to the uterus. Reaching its final destination at embryonic day four and a half (E4.5), the mouse embryo comes for the first time in direct contact with the maternal tissues and initiates implantation into the uterine wall. In turn, the uterine stroma (decidua) engulfs and conceals the embryo, making it inaccessible for direct observations and experimental manipulations. Thus, periimplantation development is largely unexplored and probably the most enigmatic period of mammalian embryogenesis. In a very short period of time, just within 24 h, the hollow-shaped mouse embryo (blastocyst) radically changes its tissue-scale architecture, transforming into a postimplantation conceptus (egg cylinder). This morphogenetic transition is associated with a burst of cell proliferation and progressive changes in the cell fate of the embryonic and the supporting extraembryonic lineages. Understanding the underlying cellular mechanisms of embryonic morphogenesis and identifying the molecular circuits that synchronise this process with the cell fate progression are the main objectives of this project. Our research also expands beyond the embryo-intrinsic regulation of the per-implantation embryogenesis and explores the hidden dynamics of the first embryo-maternal interactions at the implantation site.

Publications

• Functional and clinical characterization of the alternatively spliced isoform AML1-ETO9a in adult patients with translocation t(8;21)(q22;q22.1) acute myeloid leukemia (AML). Leukemia, 34(2), 630-634.
  Agrawal, Mridul; Schwarz, Peggy; Giaimo, Benedetto Daniele; Bedzhov, Ivan; Corbacioglu, Andrea; Weber, Daniela; Gaidzik, Verena I.; Jahn, Nikolaus; Rücker, Frank G.; Schroeder, Thomas; Kindler, Thomas; Wattad, Mohammed; Götze, Katharina; Lübbert, Michael; Salwender, Hans; Ringhoffer, Mark; Lange, Elisabeth; Koller, Elisabeth; Thol, Felicitas ... & Oswald, Franz
  
• Isolation and Culture of Periimplantation and Early Postimplantation Mouse Embryos. Methods in Molecular Biology, 373-382.
  Govindasamy, Niraimathi & Bedzhov, Ivan
  
• Test-tube embryos - mouse and human development in vitro to blastocyst stage and beyond. The International Journal of Developmental Biology, 63(3-4-5), 203-215.
  Govindasamy, Niraimathi; Duethorn, Binyamin; Oezgueldez, Hatice O.; Kim, Yung S. & Bedzhov, Ivan
  
• In Vitro Culture of Mouse Blastocysts to the Egg Cylinder Stage via Mural Trophectoderm Excision. Methods in Molecular Biology, 31-40.
  Ozguldez, Hatice O. & Bedzhov, Ivan
  
• Placental gene editing via trophectoderm-specific Tat-Cre/loxP recombination. Development.
  Ozguldez, Hatice O.; Fan, Rui & Bedzhov, Ivan
  
• Wnt/Beta-catenin/Esrrb signalling controls the tissue-scale reorganization and maintenance of the pluripotent lineage during murine embryonic diapause. Nature Communications, 11(1).
  Fan, Rui; Kim, Yung Su; Wu, Jie; Chen, Rui; Zeuschner, Dagmar; Mildner, Karina; Adachi, Kenjiro; Wu, Guangming; Galatidou, Styliani; Li, Jianhua; Schöler, Hans R.; Leidel, Sebastian A. & Bedzhov, Ivan
  
• 3D biomimetic platform reveals the first interactions of the embryo and the maternal blood vessels. Developmental Cell, 56(23), 3276-3287.e8.
  Govindasamy, Niraimathi; Long, Hongyan; Jeong, Hyun-Woo; Raman, Ratish; Özcifci, Burak; Probst, Simone; Arnold, Sebastian J.; Riehemann, Kristina; Ranga, Adrian; Adams, Ralf H.; Trappmann, Britta & Bedzhov, Ivan
  
• Deciphering epiblast lumenogenesis reveals proamniotic cavity control of embryo growth and patterning. Science Advances, 7(11).
  Kim, Yung Su; Fan, Rui; Kremer, Ludmila; Kuempel-Rink, Nannette; Mildner, Karina; Zeuschner, Dagmar; Hekking, Liesbeth; Stehling, Martin & Bedzhov, Ivan
  
• PCT/EP2021/066945 Generation of trophectoderm-like cells and assembly of trophectoderm-like vesicles and synthetic embryoids
  Sathyanarayanan & Bedzhov
  
• Ronin governs the metabolic capacity of the embryonic lineage for post‐implantation development. EMBO reports, 22(11).
  Salewskij, Kirill; Gross‐Thebing, Theresa; Ing‐Simmons, Elizabeth; Duethorn, Binyamin; Rieger, Bettina; Fan, Rui; Chen, Rui; Govindasamy, Niraimathi; Brinkmann, Heike; Kremer, Ludmila; Kuempel‐Rink, Nannette; Mildner, Karina; Zeuschner, Dagmar; Stehling, Martin; Dejosez, Marion; Zwaka, Thomas P.; Schöler, Hans R.; Busch, Karin B.; Vaquerizas, Juan M. & Bedzhov, Ivan
  
• A balanced Oct4 interactome is crucial for maintaining pluripotency. Science Advances, 8(7).
  Han, Dong; Wu, Guangming; Chen, Rui; Drexler, Hannes C. A.; MacCarthy, Caitlin M.; Kim, Kee-Pyo; Adachi, Kenjiro; Gerovska, Daniela; Mavrommatis, Lampros; Bedzhov, Ivan; Araúzo-Bravo, Marcos J. & Schöler, Hans R.
  
• Early developmental plasticity enables the induction of an intermediate extraembryonic cell state. Science Advances, 8(44).
  Sathyanarayanan, Anusha; Ing-Simmons, Elizabeth; Chen, Rui; Jeong, Hyun-Woo; Ozguldez, Hatice O.; Fan, Rui; Duethorn, Binyamin; Kim, Kee-Pyo; Kim, Yung Su; Stehling, Martin; Brinkmann, Heike; Schöler, Hans R.; Adams, Ralf H.; Vaquerizas, Juan M. & Bedzhov, Ivan
  
• Induction of osteogenesis by bone-targeted Notch activation. eLife, 11.
  Xu, Cong; Dinh, Van Vuong; Kruse, Kai; Jeong, Hyun-Woo; Watson, Emma C.; Adams, Susanne; Berkenfeld, Frank; Stehling, Martin; Rasouli, Seyed Javad; Fan, Rui; Chen, Rui; Bedzhov, Ivan; Chen, Qi; Kato, Katsuhiro; Pitulescu, Mara E. & Adams, Ralf H.
  
• Lima1 mediates the pluripotency control of membrane dynamics and cellular metabolism. Nature Communications, 13(1).
  Duethorn, Binyamin; Groll, Fabian; Rieger, Bettina; Drexler, Hannes C. A.; Brinkmann, Heike; Kremer, Ludmila; Stehling, Martin; Borowski, Marie-Theres; Mildner, Karina; Zeuschner, Dagmar; Zernicka-Goetz, Magdalena; Stemmler, Marc P.; Busch, Karin B.; Vaquerizas, Juan M. & Bedzhov, Ivan
  
• Mechanisms of formation and functions of the early embryonic cavities. Seminars in Cell & Developmental Biology, 131, 110-116.
  Kim, Yung Su & Bedzhov, Ivan
  
• Rap1 controls epiblast morphogenesis in sync with the pluripotency states transition. Developmental Cell, 57(16), 1937-1956.e8.
  Kim, Yung Su; Fan, Rui; Lith, Sanne C.; Dicke, Ann-Kristin; Drexler, Hannes C.A.; Kremer, Ludmila; Kuempel-Rink, Nannette; Hekking, Liesbeth; Stehling, Martin & Bedzhov, Ivan
  
• Tissue clearing may alter emission and absorption properties of common fluorophores. Scientific Reports, 12(1).
  Eliat, Farsam; Sohn, Rebecca; Renner, Henrik; Kagermeier, Theresa; Volkery, Stefan; Brinkmann, Heike; Kirschnick, Nils; Kiefer, Friedemann; Grabos, Martha; Becker, Katharina; Bedzhov, Ivan; Schöler, Hans R. & Bruder, Jan M.
  
• Polarity inversion reorganizes the stem cell compartment of the trophoblast lineage. Cell Reports, 42(4), 112313.
  Ozguldez, Hatice O.; Govindasamy, Niraimathi; Fan, Rui; Long, Hongyan; Mildner, Karina; Zeuschner, Dagmar; Trappmann, Britta; Ranga, Adrian & Bedzhov, Ivan