The long-term goal of our work is to understand the development of cell lineages and patterning in the early mammalian embryo. We use mouse embryos as a model system because this allows us to combine cell biological and molecular genetic approaches with state of the art imaging to study development in a system that is close to our own human development. Our research address three questions:

Pluripotency and Cell-fate acquisition: Early embryonic cells are born equal with their world full of choices but over time their development will become restricted. We study the processes that mediate the transition from pluripotency towards differentiation with a particular focus on the interplay between cell polarity, cell position and developmental history of cells. We wish to understand how together these factors affect chromatin organization and behaviour of transcription factors and hence developmental processes.

Asymmetric and Symmetric divisions: Development begins with the drastically asymmetric divisions of the oocyte but, upon sperm entry, cell divisions become symmetric for several rounds. When cells polarise, asymmetric divisions are required once again in order to send two generations of daughter cells into the interior of the embryo as part of the first two cell fate decisions. We are interested in the processes that break embryo symmetry and direct spindle orientation during these asymmetric and symmetric divisions in the oocyte and embryo.

Pattern formation: To build the body it is necessary to integrate the development of complex populations of cells within the embryo. To understand these processes in early development, we wish to follow the genesis of the first signaling centers and to determine how they coordinate the behaviour of other cells. To this end we are exploring events that take place during embryo implantation when these signalling centres first emerge and start to function. This has only just become possible using a system we have developed to culture and image development through the implantation stages. It allows us direct observations of the cell dynamics and interactions that drive the establishment of distinct cell lineages and anterior-posterior pattern.

2-cell stage mouse embryo after the division. Microtubules in green, chromatin in magenta. (Image by Bedra Sharif)

Time course of an 8-16 cell stage embryo in which one cell is dividing asymmetrically, giving ise to an outside and inside cell. Chromosomes visualised in green, cell membranes in red. (Image by Sam Morris)

3D reconstruction of mouse blastocyst. Yellow: pluripotent cells of the inner cell mass; blue and green: outside cells of trophectoderm. (Image from Emlyn Parfitt)

Plain English:
We study the development of the mouse embryo because it is an excellent model for the human embryo. In contrast to embryos of most non-mammalian species where development follows a fixed set of instructions, cell fate is flexible in mammalian embryos enabling them to recover from perturbations.  However, early mammalian embryos do not appear to be simply a uniform balls of cells; their cells do show some preferences for adopting certain positions that will in turn govern what they develop into.  We are looking at how cells come to occupy different positions within the embryo and how this influences their development to activate sets of molecular switches.  We also want to know whether and how “forcing” a cell along a particular developmental pathway will cause it to move to a place more suited to its new way of life.  Although the embryo appears quite primitive before it has implanted into the wall of the mother’s womb, in fact it comprises some four cell-types.  A few cells from one cell-type will develop into a cluster that shortly after implantation will send out the signal to make the head-end of the body.  We wish to know the origins of these cells and how their development is influenced by surrounding structures.

Selected publications:

• Morris SA, Teo RT, Li H, Robson P, Glover DM and Zernicka-Goetz M (2010) Origin and formation of the first two distinct cell types of the inner cell mass in the mouse embryo. PNAS U S A. 6;107(14):6364-9

• Bruce AW and Zernicka-Goetz M (2010) Developmental control of the early mammalian embryo: competition among heterogeneous cells that biases cell fate Curr Opin Genet Dev. 20(5):485-91

• Sharif B, Na J, Lykke-Hartmann K, McLaughlin SM, Laue E, Glover DM and Zernicka-Goetz M (2010). The Chromosome Passenger Complex is required for Fidelity of Chromosome Transmission and Cytokinesis in Meiosis of mouse Oocytes. J Cell Sci, 15;123:4292-30

• Jedrusik A, Parfitt DE, Guo G, Skamagki M, Grabarek JB, Johnson MH, Robson P and Zernicka-Goetz M (2008) Role of Cdx2 and cell polarity in cell allocation and specification of trophectoderm and inner cell mass in the mouse embryo. Genes Dev. 22(19):2692-706

• Bischoff M, Parfitt DE and Zernicka-Goetz M (2008) Formation of the embryonic-abembryonic axis of the mouse blastocyst: relationships between orientation of early cleavage divisions and pattern of symmetric/asymmetric divisions Development 135(5) 953-62 6.

• Torres-Padilla ME, Parfitt DE, Kouzarides T and Zernicka-Goetz M (2007) Histone arginine methylation regulates pluripotency in the early mouse embryo. Nature 445, 214-218 7.

• Torres-Padilla ME and Zernicka-Goetz M (2006) Role of TIF1 as a modulator of embryonic transcription in the mouse zygote. J Cell Biol, 174, 329-338 8.

3D reconstruction of mouse embryo 3.5 day after fertilisation; pluripotent cells (ICM) in red, trophectoderm in blue (Image by Agnieszka Jedrusik)

• Na J and Zernicka-Goetz M (2006) Asymmetric positioning and organization of the meiotic spindle of mouse oocytes requires CDC42 function Current Biology 16, 1249-125 9.

• Plusa B, Frankenberg S, Chalmers A, Hadjantonakis A-K, Moore C A, Papalopulu N, Papaloannou VE, Glover DM and Zernicka-Goetz M (2005) Downregulation of Par3 and aPKC function directs cells towards the ICM in the preimplantation mouse embryo J of Cell Sci 118, 505-515 10.

• Plusa B, Hajantonakis A-K, Gray D, Piotrowska-Nitsche K, Jedrusik A, Papaloannou VE, Glover DM and Zernicka-Goetz M (2005) The first cleavage of the mouse zygote predicts the blastocyst axis. Nature 434, 391-395 11.

• Wang QT, Piotrowska K, Ciemerych MA, Milenkovic L, Scott MP, Davis RW and Zernicka-Goetz M. (2004) A genome-wide study of gene activity reveals developmental signaling pathways in the preimplantation mouse embryo. Dev Cell. 6(1):133-44.

3D reconstruction of an early mouse blastocyst. Cdx2 was over-expressed in half the embryo at the 2-cell stage. The resulting cells contribute disproportionally to the trophectoderm (red cells) of the blastocyst. Cells from the non-injected cell are in blue. (Image by Agnieszka Jedrusik)