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The role of dll4 in haematopoietic stem cell emergence

  • Full or part time
  • Application Deadline
    Sunday, January 12, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Applications are invited for a 4-year PhD Studentship within the Midlands Integrative Biosciences Training Partnership (MIBTP), fully funded by the BBSRC starting October 2020

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. They arise from the haemogenic endothelium (HE), a specialized subset of endothelial cells located in the floor of the main embryonic artery, the dorsal aorta. 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 a HE-like intermediate 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 from the HE. A major player in determining the arterial and haemogenic endothelial fates is the Notch signalling pathway1. For example, the ratio between the levels of Notch ligands Dll4 and Jag1 in endothelial cells is thought to define the arterial vs haemogenic fate: Jag1 determines the haematopoietic fate whereas Dll4 drives the arterial fate2. However, we and others have recently uncovered evidence suggesting that establishing the (aortic) arterial cell fate is a pre-requisite for the formation of HE3,4.

Objectives
To study the role of the Notch ligand Dll4 in the formation of HE and subsequent production of HSCs. To achieve this, we will:
1. Generate transgenic lines to drive Cre recombinase specifically in arterial endothelial (dll4-Cre) and HE cells (gata2b-Cre) and perform lineage tracing in vivo to identify the haematopoietic cell populations that derive from dll4+ (arterial) or gata2b+ (HE) cells. Characterization of these haematopoietic cells will be accomplished by single cell epigenetic and transcriptional profiling of the labelled cells.
2. Determine how dll4 contributes to HE formation. For this, we will compare gene expression between wildtype and dll4 mutants by RNAseq using a transgenic line that allows separation of arterial and HE cells.

Here we combine classical developmental biology techniques with lineage tracing, genome editing and cutting edge single cell transcriptomics and epigenomics 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, transcriptomics or epigenetics. 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 () to discuss the project before applying. Additional projects are available in the lab.
This project can be found under the Theme ‘Stem Cells’ here (https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/stem_cells/dll4).

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. Detailed instructions for applicants, academic requirements and eligibility criteria can be found in the University of Birmingham and University of Warwick websites: View Website
View Website

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 Gama-Norton, L. et al. Notch signal strength controls cell fate in the haemogenic endothelium. Nat Commun 6, 8510, doi:10.1038/ncomms9510 (2015).
3 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).
4 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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