WNT signalling in the transition from naïve pluripotency to early cell lineages in human development
Lead Research Organisation:
University of Aberdeen
Department Name: Sch of Medicine, Medical Sci & Nutrition
Abstract
We are all naturally interested in how we develop as an early embryo from the sperm and egg of our parents. But for obvious ethical reasons, we cannot perform on humans the experiments needed to properly investigate early embryogenesis. That is why experimental animal model systems, particularly early mouse embryos, have been used to inform us about processes of early animal development. It has been generally assumed that the mechanisms governing early mouse embryo development will be more or less directly applicable to early human embryos. (To date, these assumptions have been partially correct, but notable exceptions to early human embryonic development are beginning to be uncovered, see below).
With advances in human fertilisation technology, surplus human embryos have allowed the identification and culturing in the laboratory of very early (naïve) embryonic stem cell lines for important biomedical research. These stem cell-based models can now be used in the laboratory to study aspects of early human embryo development. Generally, much of what has been learned from mice indeed appears similar in these human early embryonic stem cells. But there appear to be unexpected differences between mouse and human, particularly in a molecular mechanism called WNT signalling. WNT cell signalling allows embryonic cells to communicate to each other. WNT signalling appears to regulate early embryo development differently in mouse and human; particularly while controlling whether embryonic stem cells will remain embryonic stem cells on the one hand versus on the other hand, changing their identity and proceeding to start building the organs of the embryo.
Now is therefore the perfect time to investigate WNT signalling function in these new stem cell models of very early human development.
1. We will study how the WNT signalling mechanism operates in early human embryonic cells to control their decision between remaining stem cells (stemness) for a while versus adopting one of several extra-embryonic or embryonic cell fates that they will later follow. (Extra-embryonic tissues are essential for human and mammalian animal development, since extra-embryonic tissues will form the placenta and yolk sac, which both pattern and feed the developing foetus (unborn baby)).
2. We will study how WNT signalling controls specific genes (direct targets), which in turn then regulate stemness and subsequent cell fate.
3. We will study how WNT signalling interacts with other control mechanisms to coordinate stemness and adoption of these subsequent embryonic/extra-embryonic paths.
Our focus for this ambitious research project is to develop a new paradigm for how this ancient WNT cell signalling cascade guides early human development. Our findings will subsequently require a direct comparison to mouse embryos and as far as appropriate in human embryos. This comparison will allow us to understand the similarities and differences between mouse and human early development, and this will furthermore elucidate which aspects of knowledge gained from the mouse (and other research animal models) can and which should not directly be applied to human development. The insights gained will eventually have overarching implications for the study of human fertility, miscarriages, congenital birth defects, and health more generally.
With advances in human fertilisation technology, surplus human embryos have allowed the identification and culturing in the laboratory of very early (naïve) embryonic stem cell lines for important biomedical research. These stem cell-based models can now be used in the laboratory to study aspects of early human embryo development. Generally, much of what has been learned from mice indeed appears similar in these human early embryonic stem cells. But there appear to be unexpected differences between mouse and human, particularly in a molecular mechanism called WNT signalling. WNT cell signalling allows embryonic cells to communicate to each other. WNT signalling appears to regulate early embryo development differently in mouse and human; particularly while controlling whether embryonic stem cells will remain embryonic stem cells on the one hand versus on the other hand, changing their identity and proceeding to start building the organs of the embryo.
Now is therefore the perfect time to investigate WNT signalling function in these new stem cell models of very early human development.
1. We will study how the WNT signalling mechanism operates in early human embryonic cells to control their decision between remaining stem cells (stemness) for a while versus adopting one of several extra-embryonic or embryonic cell fates that they will later follow. (Extra-embryonic tissues are essential for human and mammalian animal development, since extra-embryonic tissues will form the placenta and yolk sac, which both pattern and feed the developing foetus (unborn baby)).
2. We will study how WNT signalling controls specific genes (direct targets), which in turn then regulate stemness and subsequent cell fate.
3. We will study how WNT signalling interacts with other control mechanisms to coordinate stemness and adoption of these subsequent embryonic/extra-embryonic paths.
Our focus for this ambitious research project is to develop a new paradigm for how this ancient WNT cell signalling cascade guides early human development. Our findings will subsequently require a direct comparison to mouse embryos and as far as appropriate in human embryos. This comparison will allow us to understand the similarities and differences between mouse and human early development, and this will furthermore elucidate which aspects of knowledge gained from the mouse (and other research animal models) can and which should not directly be applied to human development. The insights gained will eventually have overarching implications for the study of human fertility, miscarriages, congenital birth defects, and health more generally.
Technical Summary
For good reasons the mouse paradigm dominates our current understanding of early mammalian development; yet fundamental differences have recently been discovered between earliest stages of mouse and human. Particularly significant are differences relating to Wnt/beta-catenin signalling: differences in the requirement of Wnt/beta-catenin for naïve pluripotency, and in the expression patterns of TCF/LEF genes. Furthermore, current ideas about Wnt function in early human development come from manipulating Wnt signalling in a few cell lines, often using small molecule inhibitors with potentially pleiotropic effects. Overall, there is substantial uncertainty about how Wnt signalling contributes to regulating the transition of human embryonic cells from naïve pluripotency to specific early differentiation lineages.
Here we bring together a team of researchers with complementary expertise, to investigate the early function of Wnt/beta-catenin signalling in human embryonic development. This work takes advantage of new human naïve pluripotent embryonic stem (HNES) cells as experimental models to address three fundamental issues:
1. We will monitor in which cell lineages and at which stage Wnt/beta-catenin signalling is active, and relevant Wnt signalling molecules are expressed.
2. We will identify direct Wnt/beta-catenin target genes at the relevant stages and in specific cell lineages by combining single-cell transcriptomic and genomic analysis.
3. We will examine how Wnt/beta-catenin signalling is integrated with other regulators to control cellular transition from human naïve pluripotency to early embryonic lineages.
This research project will test and advance our understanding of the earliest stages of human embryonic development, by resolving current debate about the role of Wnt/beta-catenin signalling. It will also provide a platform for future studies to build a new paradigm about early human development.
Here we bring together a team of researchers with complementary expertise, to investigate the early function of Wnt/beta-catenin signalling in human embryonic development. This work takes advantage of new human naïve pluripotent embryonic stem (HNES) cells as experimental models to address three fundamental issues:
1. We will monitor in which cell lineages and at which stage Wnt/beta-catenin signalling is active, and relevant Wnt signalling molecules are expressed.
2. We will identify direct Wnt/beta-catenin target genes at the relevant stages and in specific cell lineages by combining single-cell transcriptomic and genomic analysis.
3. We will examine how Wnt/beta-catenin signalling is integrated with other regulators to control cellular transition from human naïve pluripotency to early embryonic lineages.
This research project will test and advance our understanding of the earliest stages of human embryonic development, by resolving current debate about the role of Wnt/beta-catenin signalling. It will also provide a platform for future studies to build a new paradigm about early human development.
