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Embryonic and extraembryonic partnership: requisite for successful pregnancy

Embryonic and extraembryonic partnership: requisite for successful pregnancy  
Supervisor: Prof. Magdalena Zernicka-Goetz

Mammalian Embryo and Stem Cell Group, PDN Department, CTR, University of Cambridge.  http://www.pdn.cam.ac.uk/zernickagoetzlab/

Development of mammalian embryos is unusual as it is first devoted to the establishment of not only embryonic, but also extra-embryonic tissues. The embryonic tissue will undertake a series of cell fate decisions to give rise to an entire new organism while the extra-embryonic tissues will guide this process, and finally will build a placenta to enable contact between the developing organism and the mother.  Perfect partnership between these embryonic and extra-embryonic tissues is crucial for successful pregnancy. The aim of this project is to dissect this partnership.

 To this end, this study will take advantage of two new developments in Magda Zernicka-Goetz’s group. First, a new in vitro culture system that allows mouse and human embryos to develop outside the mother’s body until gastrulation (Bedzhov and Zernicka-Goetz, Cell 2014; Bedzhov et al., Nature Protocols; Shahbazi et al., Nature Cell Biology, 2016; Deglincerti et al., Nature 2016). Second, a new 3D stem cell model that recapitulate critical aspects of embryo development allowing embryonic stem cells (ESCs) and extra-embryonic trophoblast stem cells (TSCs) interact and generate “synthetic ET embryoids” (Harrison et al., unpublished; Shahbazi et al., Nature Cell Biology, 2016). Strikingly, these synthetic ET embryoids recapitulate the morphology of post-implantation embryos and the spatio-temporal expression of key cell fate markers indicating initiation of gastrulation and specification of primordial germ cells on the boundary between embryonic and extra-embryonic tissues.

The main aims of this project are:

(1) to identify and directly compare single cell gene expression patterns (single-cell RNA seq) in the synthetic ET embryoids with normal embryos at successive stages of implantation and post-implantation development. 

(2) to determine novel signalling interactions between two distinct stem cell types (ESCs and TSCs) that lead to symmetry breaking by genetically modifying synthetic ET-embryoids and comparing their embryonic-extraembryonic interactions with those of normal ex vivo development. 

(3) to develop new stem cell models by generating 3D-models of embryonic and extraembryonic stem cells from other mammalian species to compare their morphogenesis. 

This PhD project will bring long-awaited insight into human embryo development and stem cell biology and early pregnancy loss and will thus have powerful translational impact.

 For Further Information please contact me:
Email: mz205@cam.ac.uk
Telephone:  44(0)1223 763291

References: 

  1. Shahbazi MN Jedrusik A, VuoristoS, Recher G, Hupalowska A, Bolton V, Fogarty N, Campbell A, Gasparini LD, Ilic D, Khalaf Y NiakanKK, Fishel S and Zernicka-GoetzM.  Human embryo implantation morphogenesis and self-organization in the absence of maternal tissues. Nature Cell Biology, 18(6):700-8. doi: 10.1038/ncb3347
  2. Deglincerti A, Croft GF, Pietila LN, Zernicka-Goetz M, Siggia ED, and Brivanlou A. Self-organization of the in vitro attached human embryo. Nature, 4;533(7602):251-4. doi: 10.1038/nature17948
  3. Bedzhov I, Leung CY, Bialecka M, Zernicka-Goetz M. (2014). In vitro culture of mouse blastocysts beyond the implantation stages. Nature Protocols 9(12):2732-9. doi: 10.1038/nprot.2014.186. PMID: 25356584
  4. Bedzhov I, Graham SJ, Leung CY and Zernicka-Goetz M (2014). Developmental plasticity, cell fate specification and morphogenesis in the early mouse embryo. Philos Trans R Soc Lond B Biol Sci. 369(1657). pii: 20130538 doi: 10.1038/nprot.2014.186 PMID: 25349447
  5. Bedzhov I and Zernicka-Goetz M. (2014). Self-organizing properties of mouse pluripotent cells initiate morphogenesis upon implantation.Cell.156(5):1032-44.doi: 10.1016/j.cell.2014.01.023. PMID: 24529478