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EASTBIO: Wnt signalling regulates early human embryonic stem cell development


   School of Medicine, Medical Sciences & Nutrition

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  Prof S Hoppler, Prof Jennifer Nichols  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

This fully funded, 4-year PhD project is part of a competition funded by the BBSRC EASTBIO Doctoral Training Partnership

Human life starts from a single fertilised egg, which subsequently divides many times, but remarkably, very early embryonic cells contain all the instructions to build all subsequent specialised cells of the embryo and then the body; they are pluripotent. Early embryonic cells signal to each other to allocate different cell fates and embryonic tissues, such as different germ layers of the embryonic and extraembryonic tissues.

Investigation using accessible model systems, such as the mouse, identified Wnt signalling among important cell-to-cell signalling mechanisms that regulate this cell differentiation among stem cells in early mammalian embryos. Wnt signalling between embryonic cells regulates tissue- and cell-lineage-specific downstream gene expression via nuclear beta-catenin protein and TCF/LEF Transcription Factors.

Only very recently has it become possible to study these very early stages in stem cell models of human embryogenesis and there appear to be some important differences between the mouse model system and early human embryonic development. Our hypothesis is that there are important differences in Wnt signalling; particularly differences in the expression of TCF/LEF genes.

This studentship offers an exciting opportunity to investigate these specific features of Wnt signalling in models of early human development in this collaboration between an expert research group on early human development and stem cells in Edinburgh and a Wnt signalling research group in Aberdeen.

The student will initially collect in Edinburgh stage- and tissue-specific samples and analyse in Aberdeen in which tissue and cell lineage and at which early embryonic stage Wnt signalling is active in models of early human development. This will be done by monitoring Wnt-regulated nuclear translocation of the beta-catenin protein (e.g. with Immunofluorescence). Similar samples will be analysed to precisely map expression of TCF/LEF transcription factor genes and of specific TCF isoforms (e.g. with rtPCR and in-situ hybridisation). The expression of candidate direct target genes of Wnt/beta-catenin/TCF signalling will also be explored with these human samples.

This detailed analysis will allow the team to formulate more precise hypotheses about human-specific functions of Wnt signalling in early embryogenesis. We will test these hypotheses in suitable human stem cell models of early embryogenesis by applying small molecule inhibitors to activate or inhibit Wnt/beta-catenin signalling and by knocking out (or knocking down) and by overexpressing specific TCF/LEF proteins. These experiments will then be analysed by monitoring expression of potential Wnt target genes and tissue- and cell-lineage specific marker genes.

This studentship will provide a better understanding of early human development which will inform fertility treatments and other Wnt-related health issues. 

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ELIGIBILITY:

  • Applicants should hold a minimum of a 2:1 UK Honours degree (or international equivalent) in a relevant subject. Those with a 2:2 UK Honours degree (or international equivalent) may be considered, provided they have (or are expected to achieve) a Distinction or Commendation at master’s level.
  • All students must meet the eligibility criteria as outlined in the UKRI guidance on UK, EU and international candidates.  This guidance should be read in conjunction with the UKRI Training Grant Terms and Conditions, esp. TGC 5.2 & Annex B.

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APPLICATION PROCEUDRE:

  • Please visit this page for full application information: How to apply | eastbio (eastscotbiodtp.ac.uk)
  • Please send your completed EASTBIO application form, along with academic transcripts to Alison Innes at: [Email Address Removed]
  • Two references should be provided by the deadline using the EASTBIO reference form. References should be sent to [Email Address Removed]
  • Unfortunately, due to workload constraints, we cannot consider incomplete applications.
  • CV's submitted directly through a FindAPhD enquiry WILL NOT be considered.

Funding Notes

This fully funded, 4-year PhD project is part of a competition funded by the EASTBIO BBSRC Doctoral Training Partnership.
This opportunity is open to UK and International students (The proportion of international students appointed through the EASTBIO DTP is capped at 30% by UKRI BBSRC).
EASTBIO studentships includes a UKRI doctoral stipend (estimated at £17,668 for the 2023/2024 academic year), plus a training grant of £5,000 per annum (year 1-3; £1,500 year 4) and a travel/conference grant of £230 per annum.
EASTBIO does not provide funding to cover visa and associated healthcare surcharges for international students.

References

1. Afouda et al. (2020) Foxh1/Nodal Defines Context-Specific Direct Maternal Wnt/β-Catenin Target Gene Regulation in Early Development. iScience, doi: 10.1016/j.isci.2020.101314
2. Guo et al. (2021) Human naive epiblast cells possess unrestricted lineage potential. Cell Stem Cell. doi: 10.1016/j.stem.2021.02.025
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