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*EASTBIO* Control of the ParaHox genes in chordate evolution and development

  • Full or part time
    Dr D E K Ferrier
    Prof J K Dale
  • Application Deadline
    Sunday, January 05, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

BBSRC Thematic Group: Frontier Bioscience
This project will use a comparative approach to dissect regulatory mechanisms of the chordate ParaHox genes (Gsx, Xlox/Pdx1 and Cdx), analysing regulatory elements of these genes in both the invertebrate sea squirt Ciona intestinalis and the vertebrate Gallus gallus (chicken).

ParaHox genes are the evolutionary sisters to the Hox genes, and like their sisters are important components of axial patterning, mainly in the central nervous system and gut. They also tend to have a clustered organisation in the genome that is likely linked to how the genes are regulated. Mis-regulation of ParaHox genes can cause diseases such as diabetes and colon cancer.

A major open question is whether an ancestral mechanism for Hox/ParaHox regulation can be deduced, which would provide both a fundamental insight into animal development and reveal the starting point from which the current regulatory diversity evolved. Understanding ParaHox regulation is a key route to achieving this goal. Since the split into Hox and ParaHox clusters occurred early in animal evolution [1], comparisons of ParaHox and Hox regulation can potentially reveal what is conserved between these sister clusters and hence what mechanisms were involved in control of these genes in the earliest animals, with these fundamental mechanisms then underpinning all subsequent evolution.

In this project, we will integrate data from both invertebrate and vertebrate systems, capitalizing on the power of the comparative approach to deduce underlying fundamental aspects of body axis patterning by regulation of the ParaHox genes. The invertebrate models will be amphioxus (Branchiostoma) with its prototypical ParaHox cluster and chordate embryogenesis, and the sea squirt Ciona intestinalis, in which large numbers of embryos can be rapidly transformed by electroporation [2] and for which large data-sets of DNA sequence and gene expression are available. The vertebrate model will be the chicken, Gallus gallus, due to its compact, intact ParaHox cluster, well-established suitability as an embryological study system and available techniques in embryo electroporation and gene expression analyses [3].

Regulatory elements will be characterised via generation of reporter genes from around the ParaHox genes of amphioxus, Ciona and chicken. This will enable direct comparison of two intact and one dispersed ParaHox clusters. Reporter construction will be aided by bioinformatic comparisons of these genomic loci across the invertebrate chordate and vertebrate genome sequences that are already available. Minimal regulatory elements will be isolated via deletion mapping of reporters and candidate transcription factors deduced via bioinformatic analyses, comparisons to expression databases and site-directed mutagenesis and/or in vitro binding assays. This will establish what regulatory factors are operating across the ParaHox genes, potentially throughout the chordate phylum, and will form the basis for comparisons to regulation of the Hox genes to establish whether the same fundamental regulatory mechanisms might be operating across the animals.

The student will obtain training in cutting-edge techniques in molecular biology, embryology, bioimaging and bioinformatics and be part of the enthusiastic and vibrant research communities in the Universities of St Andrews and Dundee, benefitting from complementary strengths, strong links and close proximity of these institutions.

Funding Notes

This project is eligible for the EASTBIO Doctoral Training Partnership: View Website

This opportunity is only open to UK nationals (or EU students who have been resident in the UK for 3+ years immediately prior to the programme start date) due to restrictions imposed by the funding body.

Apply by 5.00 pm on 5 January 2020 following the instructions on how to apply at: View Website

Please also upload the EASTBO Application Form as an additional document to the University of St Andrews online Application.

Informal inquiries to the primary supervisor are very strongly encouraged.

References

1) Fortunato, S.A.V., Adamski, M., Mendivil Ramos, O., Leininger, S., Liu, J., Ferrier, D.E.K. and Adamska, M. Calcisponges have a ParaHox gene and dynamic expression of dispersed NK homeobox genes. Nature (2014) 514: 620-623.

2) Garstang, M.G., Osborne, P.W., and Ferrier, D.E.K. TCF/Lef regulates the Gsx ParaHox gene in central nervous system development in chordates. BMC Evolutionary Biology (2016) 16: 57.

3) Wiedermann, G., Bone, R.A., Silva, J.C., Bjorklund, M., Murray, P.J. and Dale, J.K. A balance of positive and negative regulators determines the pace of the segmentation clock. eLife (2015) 4: e05842.

How good is research at University of St Andrews in Biological Sciences?

FTE Category A staff submitted: 50.45

Research output data provided by the Research Excellence Framework (REF)

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