Our lab aims to understand mechanisms by which cells establish their identity, gain and lose pluripotency and how it relates to embryo shape and size, plasticity and self-organization. To address these questions we study mouse and human embryos and build embryo models from multiple stem cell types in vitro.
Pre-patterning of the embryo, driven by spatially localized factors, is a common feature across several non-mammalian species. However mammals display regulative development and thus it was thought that the blastomeres of the embryo do not show such pre-patterning and are all totipotent. Unexpectedly, by developing lineage tracing methods and live embryo imaging, we found that blastomeres of an early embryo have distinct developmental fates and potential and heterogeneous expression of certain transcripts. We found that underlying this heterogeneity is an epigenetic modification mediated by methyltransferase CARM1, which regulates expression of master pluripotency regulators. This work has considerable importance as it demonstrated the symmetry breaking event initiating the first cell fate specification. We are now trying to uncover the origins of this cellular heterogeneity and how it guides cell fate.
Cell Competition and Embryo Plasticity
Cell within the embryo compete with each other in relation to their fitness and fate. By creating mosaic embryos, we discovered that chromosomally abnormal cells, become outcompeted by normal cells in the part of the embryo that gives rise to the body, but this is not so in the part of the embryo that creates the placenta. The development of such mosaic embryos depends on the number of chromosomally normal cells. We established the minimal number of embryonic cells that have to be established by the time of implantation to ensure successful pregnancy and how the ability to generate this number relates to cellular heterogeneity in the embryo. This work has considerable importance as it allows us now to uncover the mechanisms behind this remarkable cell competition and plasticity.
Regulation of Cell Size and Timing
When mouse and human embryos have undergone the first cleavage divisions to generate 8 cells, all cells become polarized along their animal-vegetal axis. This polarization is critical for cells to establish their fate. By experimentally changing embryo size and the expression levels of specific genes, our work uncovered the mechanisms leading to embryo polarization. We also found that by changing expression of specific genes, we can speed up development. We would now like to understand the mechanisms that control this developmental clock and how changing the embryo timing affects cell fate, pluripotency and embryo size.
Self-Organization of Stem Cells into Embryos In Vitro
The implantation stages of embryo development have been a mystery because this is when the human embryo becomes buried in the maternal tissues and so impossible to study. And yet this is developmental time when major transition in development of the embryo takes place and majority of human pregnancies fail. In order to gain insights to this developmental transition, we developed approaches to culture and image mouse and human embryos through their implantation stages in vitro. These approaches allowed us to reveal how pluripotent cells become polarized and organize themselves into a rosette that undergoes lumenogenesis in response to beta-integrin signalling from the basal membrane produced by surrounding extra-embryonic tissues. We used this method to reveal how exit from a naive state of pluripotency is essential for successive steps of morphogenesis. We now studying the importance of dynamic changes in three dimensional tissue architecture for mediating transitions between pluripotent states.
Synthetic Stem-Cell Derived Embryo Models
Our studies of natural embryogenesis have provided us with the foundations for understanding the main principles of development of mouse and human embryos and their embryonic and extra-embryonic tissues. This knowledge has allowed us to create the first synthetic embryos through assembly of different stem cell types - embryonic and extra-embryonic stem cells - that assemble into structures that recapitulate natural spatially regulated gene expression and morphogenesis to undertake gastrulation and develop to neurulation. These so-called synthetic embryos provide us with unprecedented opportunity to dissect the genetic and extracellular modules underlying development and organogenesis.
For updated research from the lab see our website: zernickagoetzlab.com
These are two embryos at the blastocyst stage, 5 days after fertilization. Different color dyes mark various cell types in the blastocysts. This 3D confocal microscope image was collected in MagdaZernicka-Goetz lab by Berna Sozen and Wonder Science processed it to give a sense of seeing from inside the hollow embryo cavity. A baby-baby's eye-view!