The molecular basis of mesoderm formation

Lead Research Organisation: The Francis Crick Institute

Abstract

My research investigates the mechanisms of early embryonic development. This is an important topic for two reasons. First, one in six couples have difficulty conceiving a child, a quarter of human conceptions are lost in the first five months, and 2% of children are born with a major genetic defect. Understanding developmental mechanisms can help alleviate these problems. Second, if we understand the mechanisms of normal embryonic development, we can use this information to help direct stem cell differentiation. Much of our work uses the accessible embryos of the frog and the zebrafish, but we also study the mouse as well as mouse and human embryonic stem cells. One of our objectives is to ask to what extent developmental mechanisms are conserved between species.

Technical Summary

This work was supported by the Francis Crick Institute which receives its core funding from the UK Medical Research Council (FC001000), the Wellcome Trust (FC001000),and Cancer Research UK (FC001000)

The different cell types of the body are formed in the right place and at the right time in response to signals that are produced by special organiser regions of the embryo. These so-called morphogens act in a concentration-dependent manner to induce the formation of different cell types at different positions within developing tissues. One of the earliest interactions of this kind is mesoderm induction, which results in the formation of organs and cell types such as heart, muscle, kidney and bone.
We use frog, zebrafish and mouse embryos to study mesoderm-inducing factors and to ask how cells respond to them. One aim is to understand how the signals exert long-range effects in the embryo, and how cells distinguish between different morphogen concentrations to activate different genes. We go on to explore how these different genes then participate in the genetic regulatory networks that result in the formation of specific cell types. This work involves extensive use of high-throughput sequencing technologies to reveal the transcriptomes of cells from the early embryo, to look at transcription factor binding sites, and to understand chromatin architecture. Through this work we have discovered that events in the very early embryo are required to allow cells to respond to inducing signals.
These early stages of development also involve dramatic changes in the cell cycle, and we are exploring the regulation of cell division at these early stages of embryogenesis.
The principles we define in the early embryo inform additional work on events in later development, including the heart and vasculature, and on the differentiation of embryonic stem cells, where we hope that our work will help direct ES cells down particular developmental pathways.

Publications

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