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EASTBIO: In Vitro Models of Large Animal Cranial Neural Crest Health and Dysfunction


College of Medicine and Veterinary Medicine

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Dr J Schoenebeck , Dr M Davey No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

The convergence of form and function is apparent in the facial skeleton, a complex 3D structure that supports feeding, respiration, olfaction, communication and defensive behaviours. The facial skeleton is produced by endochondral ossification of cartilage, a template which in turn is produced by cranial neural crest cells (CNCCs). CNCCs are a lineage of embryonic progenitors that also produce melanocytes, neurons, hair and part of the autonomic nervous system. Because of the latter’s role in the “fight or flight” response of animals, it has been proposed that reduction in neural crest function is integral to the domestication of wild animals. In fact, the autonomic nervous system’s neural crest origins underpins the “Domestication Syndrome” hypothesis1, a theory that attempts to explain morphological commonalities among domesticated animals including tameness, coat colour changes, ear flop, and reduction in facial skeleton length.

Because of their implication on speciation, domestication and health, CNCC biology and its underlying gene regulation is an area of intense study that is traditionally facilitated by various species of laboratory animal models. The findings from these models are presumed to be representative of humans and large animals, however this assumption is largely unverified due to the difficulties of acquiring and manipulating embryonic tissues for study.

Induced pluripotent stem cells (iPSCs) can help overcome the logistical and ethical difficulties of harvesting large animal embryonic tissues for scientific study. A recent example of this was the use of iPSCs to produce CNCC-like cells in vitro2. Not only do such cells express gene and epigenetics markers that are indicative of CNCCs, they also migrate and populate primordial facial tissues in xenograft transplantation experiments.

In this exciting and cross-disciplinary BBSRC Eastbio CASE 4-year PhD studentship, the appointed student will use Roslin Technologies Ltd’s novel canine iPSCs to produce and validate CNCCs. This work will describe the genomic regulatory landscape of CNCC’s including their gene expression, chromatin accessibility and epigenetic markers. In doing so, the student will functionally validate the SMOC2 intronic retrotransposon insertion, a genetic variant that is believed to cause canine brachycephaly3.

The student will
1) Use CRISPR/Cas9 to edit canine iPSCs to introduce the retrotransposon mutation, the presumed cause of canine brachycephaly.
2) Generate, characterise and validate CNCC-like cells from dog iPSCs using a variety of techniques including marker analysis and xenotransplantation.
3) Conduct ATAC-, ChIP- and RNA-seq experiments on CNCCs to generate epigenomic annotation of craniofacial regulatory elements to identify differentially expressed and differentially regulated genes that underpin CNCC specification and aberrant craniofacial development.

The student will be based at the University of Edinburgh’s Easter Bush research campus, splitting time between the Roslin Institute and Roslin Technologies, Ltd., to deliver the listed objectives. This exceptional studentship includes career development opportunities such as conference attendance and training.

Funding information and application procedures:
This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership (DTP) http://www.eastscotbiodtp.ac.uk/how-apply-0 .

EASTBIO Application and Reference Forms can be downloaded via http://www.eastscotbiodtp.ac.uk/how-apply-0

Please send your completed EASTBIO Application Form along with a copy of your academic transcripts to [Email Address Removed]

You should also ensure that two references have been send to [Email Address Removed] by the deadline using the EASTBIO Reference Form.


Funding Notes

This opportunity is open to UK and international students and provides funding covering stipend and UK level tuition fees. The University of Edinburgh covers the difference between home and international fees meaning that the EASTBIO DTP offers fully-funded studentships to all appointees. There is a cap on the number of international students the DTP recruits. It is important that we know from the outset which fees status category applicants fall under when applying to our university.

Please refer to UKRI (https://www.ukri.org/our-work/develop ing-people-and-skills/find-studentships-and-doctoral-training/get-a-studentship-to-fund-your-doctorate/) and Annex B of the UKRI Training Grant Terms and Conditions for full eligibility criteria (https://www.ukri.org/wp-content/uploads/2020/10/UKRI-291020-guidance-to-training-grant-terms-and-conditions.pdf).


References

1. Wilkins, A. S., Wrangham, R. W. & Fitch, W. T. Genetics 197, 795–808 (2014).
2. Prescott, S. L. et al. Cell 163, 68–83 (2015).
3. Marchant, T. W. et al. Curr. Biol. 27, 1573–1584.e6 (2017).
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