Award details

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

Reference	BB/V006339/1
Principal Investigator / Supervisor	Professor Andrea Streit
Co-Investigators / Co-Supervisors
Institution	King's College London
Department	Craniofacial Dev and Stem Cell Biology
Funding type	Research
Value (£)	476,229
Status	Current
Type	Research Grant
Start date	01/03/2022
End date	28/04/2025
Duration	38 months

Abstract

Unravelling the molecular control of developmental programmes remains a key question in development, stem cell biology and reprogramming. Recent advances in single cell transcriptomic and chromatin profiling have provided new avenues to address these questions establishing molecular catalogues of cells and characterising cell complexity. However, a key challenge remains to link transcriptional profiles directly to in vivo lineage decisions. Bringing together developmental and computational biology this project will tackle this challenge to investigate the molecular control of cell fate decisions in the cranial sensory nervous system. Specifically, we will - Use single cell RNAseq to characterise how cell complexity emerges as sensory progenitors become committed to olfactory, eye, ear and sensory ganglia identity. This will also allow us to determine dynamic transcriptional changes; - Use bulk and single cell ATACseq to identify changes in enhancer activity and use this information to predict upstream regulators and regulatory modules; - Use CRISPR-based cell scarring to reconstruct cell lineage decisions; sampling scarred cells for scRNAseq allows us to link transcriptome information with fate choices in vivo; - Integrate the above data to identify candidate fate determinants and test their function in vivo. This project will establish the genetic hierarchy that controls how sensory progenitors diversify and acquire their unique cell identity. We will establish the in vivo lineage tree, clonal relationship of cells and explore multipotency or lineage restriction. Our data will not only provide new understanding of fundamental mechanisms in biology, but also form the basis for cell reprogramming as well as providing a rich resource for future exploration.

Summary

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.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	Neuroscience and Behaviour, Stem Cells
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

Associated awards:

BB/V006290/1 Reconstructing fate decisions in the peripheral sensory nervous system of the head

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