Developmental plasticity, cell fate specification and morphogenesis in the mouse and human embryo
In our group we investigate molecular and cellular mechanisms underlying the specification of cell lineages and patterning. The mouse embryo is our major model system because this allows us to combine cell biological and molecular genetic approaches with live embryo imaging to study development in a system that is close to our own, human development.
Goal 1: Plasticity, Pluripotency and Cell Fate Acquisition
Early embryonic cells in mouse and human embryos are remarkably plastic, but, over time their developmental fate becomes restricted. How this change in fate is regulated is still unknown. We wish to understand the molecular steps that mediate the transition from the totipotency of the egg towards cell differentiation on one hand and towards pluripotency on the other. We have discovered a number of regulatory genes essential for cell lineage determination. These genes allow us to follow the interplay between cell polarity, cell position and developmental history of cells in fate specification, helping us to answer our question
Goal 2: Embryo polarisation and cell fate
Development begins with the drastically asymmetric divisions of the oocyte but then, following fertilisation, cells divide relatively symmetrically until the 8-cell stage. From the 8-cell stage forward division asymmetry is again required to send two generations of daughter cells into the interior of the embryo, contributing to the first two cell fate decisions. We wish to understand the processes that break embryo symmetry and govern division symmetry in the oocyte and embryo. With this aim, we are studying the events that lead to cell polarisation and how spindles become oriented within these cells that lack centrosomes.
Goal 3: Maternal to Zygotic transition and developmental potential
We aim to understand the factors essential to the correct development of the egg and the successful transition to the zygotic control of development. This involves characterising the molecular events of this transition but also requires the monitoring of development by studying cellular behaviour. This led us to establish a non-invasive and rapid method that allows us to predict, from the quality of periodic cytoplasmic movements and free calcium waves at fertilisation, which eggs have the highest chance of developing through the whole pregnancy. As this can be potentially used to select the best quality embryos for transfer to would-be-mothers, we are collaborating with IVF clinics to assess the value of this approach.
Goal 4: Self-organisation of stem cells into embryos
We wish to understand the processes that integrate the development of populations of different cell types into an organism. Prior to its implantation into the uterus, the mammalian embryo comprises three cell types that begin to be sculpted into an embryo with identifiable parts during implantation, a mysterious process because it is hidden from view. We have recently succeeded in overcoming this limitation by developing an efficient in vitro culture system that allows imaging development from pre- to post-implantation stages outside the body of the mother. In this way we can follow the first morphogenetic steps taken by the pluripotent cell lineages and neighbouring extra-embryonic lineages and we have learnt how to mimic several of these using ES cells. Using this system, we wish to understand the developmental dynamics of individual and groups of cells and the signals that define the positional identity of cells as the embryo continues to develop.
Goal 5: Human embryo development
The lab made a major breakthrough in 2016 by describing conditions enabling human embryos to be cultured beyond the point of implantation to gastrulation, twice as long as previously possible. This enabled us to study the first stages of the re-organisation of the pluripotent epiblast in the beginnings of proamniotic cavity formation. It allowed us to uncover defects in the development of embryos identified as carrying common aneuploidies in the clinic. Most recently we have been able to use this approach to identify a region of the hypoblast that can provide a signal signalling future anterior development. Together this has opened new doors for studying the earliest stages of our development.