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The role of dll4 in haematopoietic stem cell emergence


Institute of Cancer and Genomic Sciences

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Dr R Monteiro , Dr S Ott No more applications being accepted

About the Project

Applications are invited for a 4-year fully-funded/self-funded PhD Studentship starting October 2021

Background

Haematopoietic stem cells (HSCs) are generated during embryonic development and are responsible for the production and maintenance of all the blood lineages throughout adult life. One of the bottlenecks in the production of HSCs in vitro for substitution therapies is to determine the right conditions that mimic the embryo microenvironment and induce the correct cell that can differentiate into HSCs. The Monteiro lab is interested in understanding how endothelial and blood stem cells grow and differentiate during embryonic development and how lineage fate decisions lead to the formation of HSCs. A major player in determining haematopoietic fates is the Notch signalling pathway1. We and others have recently uncovered evidence suggesting that establishing the (aortic) arterial cell fate is a pre-requisite for the formation of HSCs2,3.

In this project, we aim to study the role of the Notch ligand Dll4 in the formation of the precursors to HSCs in the embryo. First, the student will use an existing transgenic line2 to isolate arterial and haemogenic cells to compare gene expression between wildtype and dll4 loss of function by scRNAseq. They will then generate transgenic lines to drive Cre recombinase in specific endothelial and haemogenic populations to perform lineage tracing and identify the haematopoietic cell populations that derive from arterial or haemogenic cells. Characterization of these haematopoietic cells will be accomplished by single cell transcriptional profiling of the labelled cells.

This project combines classical developmental biology techniques with lineage tracing, genome editing and cutting edge single cell transcriptomics to understand the fundamental biology regulating the formation of haematopoietic stem cells. We will establish whether the arterial fate is a pre-requisite for the formation of HSCs. That will aid ongoing efforts to produce HSCs in vitro.

Person Specification

Applicants should have a strong interest in developmental biology, haematopoiesis or transcriptomics. They should hold or realistically expect to obtain at least an Upper Second Class Honours Degree in Genetics, Biological Sciences or related subjects.

How to apply

Applicants are encouraged to contact Dr Rui Monteiro directly ([Email Address Removed]) to discuss the project before applying. This project can be found in the Theme ‘Understanding the rules of life’, under ‘Stem cells’ (https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/stem_cells). Detailed instructions for applicants, academic requirements and eligibility criteria can be found in the University of Birmingham and University of Warwick websites:
https://www.birmingham.ac.uk/research/activity/mibtp/index.aspx
https://warwick.ac.uk/mibtp/

Funding Notes

The Midlands Integrative Biosciences Training Partnership (MIBTP) is a BBSRC-funded doctoral training partnership between the universities of Warwick, Birmingham and Leicester. Successful applicants will be funded by the BBSRC, including UK fees and stipend. International students are eligible to apply, but the BBSRC does not cover international fees.
Please see application details and eligibility criteria on:
https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/application/
More details about the program on: https://warwick.ac.uk/mibtp/
https://www.birmingham.ac.uk/research/activity/mibtp/index.aspx


References

1 Butko, E., Pouget, C. & Traver, D. Complex regulation of HSC emergence by the Notch signaling pathway. Dev Biol 409, 129-138, doi:10.1016/j.ydbio.2015.11.008 (2016).

2 Bonkhofer, F. et al. Blood stem cell-forming haemogenic endothelium in zebrafish derives from arterial endothelium. Nat Commun 10, 3577, doi:10.1038/s41467-019-11423-2 (2019).

3 Uenishi, G. I. et al. NOTCH signaling specifies arterial-type definitive hemogenic endothelium from human pluripotent stem cells. Nat Commun 9, 1828, doi:10.1038/s41467-018-04134-7 (2018).


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