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EASTBIO The role of notochord progenitors in mammalian axial elongation


School of Biological Sciences

Dr V Wilson , Prof J K Dale Wednesday, January 06, 2021 Competition Funded PhD Project (Students Worldwide)

About the Project

The backbone, muscle and spinal cord are formed progressively from the neck to the tip of the tail from embryonic cells known as neuromesodermal progenitors (NMPs)1. This process is called axial elongation. Our lab, which first showed that these progenitors exist, is now investigating how NMPs are maintained, and how they choose neural versus mesodermal fates, during mammalian axial elongation. We found recently that axial elongation depends critically on the interaction of NMPs with a separate, adjacent, tiny population of progenitors for the notochord- reminiscent of a stem cell-niche interaction2. Despite their small number, the cell cycle characteristics of notochord progenitors are diverse: while most of the surrounding cells in the embryo are rapidly proliferating, only about 50% of the notochord progenitors seem to be in cycle, while their immediate descendants are quiescent.

The Dale lab has shown previously that the Notch signalling pathway is important for cell fate decisions in both notochord progenitors and NMPs. Recently they have uncovered a mechanism by which Notch signalling is regulated by the cell cycle, potentially linking this signalling pathway to the decisions made by notochord progenitors to self-renew or differentiate3.

This PhD project is a collaboration between the Wilson and Dale labs to investigate (1) how notochord progenitors are maintained, (2) how they, in turn, interact with NMPs to sustain axis elongation and (3) whether Notch is important for regulating notochord progenitor maintenance, differentiation, or both.

To do this, the student will analyse single cell RNA-seq data both in the public domain and generated in-house using pipelines we have adopted in the lab. We will ask how heterogeneous the notochord progenitor population is. In particular we will compare the expression of Notch pathway components with cell cycle regulators. This will give the student training in bioinformatics analysis.

The student will also carry out cell cycle analysis of notochord progenitors during mouse and chick development, using traditional tools such as BrdU labelling and ex vivo culture, combined with live cell imaging, providing training in embryology and image analysis.

To determine whether notochord progenitors maintain NMPs, we will generate NMPs in culture from mouse and/or human pluripotent stem cells. Notochord progenitors can be generated in culture from pluripotent stem cells, but to bypass a potentially inefficient process, we will also test whether a chordoma (notochord- derived) cell line can provide either structural or growth factor support for NMPs. If we find that notochord progenitor cells promote NMP maintenance, we will screen for molecules that do this by determining whether cells, matrix, conditioned media or a combination provide this support, and pairing this with a candidate approach gleaned from the original bioinformatic analysis. This will provide the student with training in mouse and human pluripotent stem cell culture and differentiation, as well as medium throughput screening techniques.

The project will be based mainly in Edinburgh at the Centre for Regenerative Medicine, with regular contact with Prof Dale and, for analysis related to chick embryos and Notch signalling

https://www.ed.ac.uk/regenerative-medicine/research/val-wilson
https://www.dundee.ac.uk/people/kim-dale

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Funding Notes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership View Website. This opportunity is open to UK and International students and provides funding to cover stipend and UK level tuition fees. The fee difference will be covered by the University of Edinburgh for successful international applicants. Please refer to UKRI website (View Website) and Annex B of the UKRI Training Grant Terms and Conditions (View Website) for full eligibility criteria.

References

(1) Wilson et al. (2009) Stem cells, signals and vertebrate body axis extension. Development. doi:10.1242/dev.039172
(2) Wymeersch FJ, et al. (2019) Transcriptionally dynamic progenitor populations organised around a stable niche drive axial patterning. Development. doi: 10.1242/dev.168161.
(3) Karrieri FA et al. (2019) CDK1 and CDK2 regulate NICD1 turnover and the periodicity of the segmentation clock. Embo Rep. doi: 10.15252/embr.201846436


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