Reconstructing fate decisions in the peripheral sensory nervous system of the head

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Humans and animals alike are constantly bombarded with information from our environment: smell, sound, light and colour, taste as well as less obvious stimuli like touch, pain and temperature. This information is transmitted to the brain by the sense organs and sensory ganglia in the head. While these structures are very diverse in adults, they come from common stem-cell-like progenitors during embryo development. How do cells that share a common history become different from each other? This is an exciting question with many different implications. Finding out the answer is not only important to understand how normal development works, but also to unravel the causes underlying developmental diseases, to find new ways to promote repair after cell damage and to direct stem cells to differentiate into sense organ cells.In this project, we will take advantage of new technologies that allow us to study thousands of cells at single cell level and reconstruct how cells make decisions in the living embryo. First, we will make an atlas of cells using a technology that measures gene expression in individual cells (single cell RNAseq). We will categorise cells according to the genes they express and determine the order in which new cell types appear. Second, we will determine how gene expression in different cells is controlled in time and space using an approach called ATACseq. We will use this information to predict a how cell fate decisions are regulated.Third, we will use a novel technique that has only very recently become available to reconstruct lineage trees in the embryo. Cells are marked by a unique 'scar' which is inherited as cells divide; cells are later sampled to examine their gene expression profile at single cell level. This way we can link the gene signature of a cell with its fate, establish which cells arise from the same and from different progenitors and use computational methods to uncover real lineage relationships.Finally, we will integrate all data to identify new candidate fate determinants and will test their function in the developing sensory nervous system.To achieve these aims we bring together an interdisciplinary team: the Streit group are experts in modern sensory developmental biology, while the Luscombe group has long-standing expertise in computational approaches at the forefront of biomedical research.In summary, this project will characterise the molecular properties of sense organ and ganglia progenitors and their derivatives in unprecedented depth, reconstruct their lineage relationship as well as identifying how this is controlled. The power of this project lies its interdisciplinary nature, while its impact reaches beyond developmental biology into regenerative medicine, stem cell biology and evolution.