The Generation of Positional Identity in Mesendoderm; Mechanism(s) of Lineage Specification in Vertebrate Development

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During early embryonic development, the cells of the future gut move along the midline of the embryo signalling to the nervous system. To understand the molecular instructions driving the differentiation of these cells it is necessary to isolate them from the complex and changing environments in the embryo. Being able to break down this in vivo process of lineage specification is also essential for the generation of gut associated cell types and organs from human ES cells. In this proposal, we utilise genetically modified mouse ES cells that report on differentiation towards the embryonic gut in real time. We have used this system to generate monolayer conditions for ES cell differentiation toward embryonic gut. Our ability to differentiate these cells attached to plastic means that we can easily change media components as well as following differentiation visually. This proposal exploits this system alongside embryonic models to tease apart the stages of differentiation. It contains a program of work that is both focused on identifying new determinants and understanding how these determinants drive differentiation. This proposal will provide basic mechanistic insight into developmental biology and define conditions for the efficient differentiation of ES cells towards organs like the liver and pancreas.