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The Clinical Genetics Group is one the world’s leading laboratories working on craniosynostosis, the premature closure of one or more of the cranial sutures of the skull. This is a relatively common condition affecting 1 in 2,250 babies, which requires major operations to rearrange the skull bones to avoid problems like increased pressure on the brain. Whilst human molecular genetics has been very successful at identifying many of the common causes of craniosynostosis, we still know very little about what happens biologically in the cranial sutures themselves.

These structures, narrow gaps between the skull bones filled with cells and fibrous tissue, must achieve a delicate balancing act of enabling growth of new bone at the margins of the suture, whilst also ensuring that the mid-part of the suture remains open along its entire length. This project represents an exciting opportunity to explore how the suture works by mapping out the cellular hierarchy of activities from undifferentiated stem cell to fully formed osteoblast. You will exploit the state-of-the-art facilities available in the WIMM for fluorescence-activated cell sorting (FACS), single cell transcriptomics and microscopy, and apply your discoveries to understand the mechanisms of craniosynostosis in two mouse models, caused by mutations in Zic1 and Erf, available in our laboratory.

Training Opportunities

Following techniques established in the laboratory, you will isolate single cells from mouse and human cranial sutures at different developmental stages, and carry out single cell RNA sequencing. There will be an opportunity to learn the bioinformatic tools used to cluster cells with similar transcriptomic profiles. This approach will identify specific markers (genes) that define cell types and the initial characterisation will involve visualising these populations within intact sutures using in situ hybridisation analysis and microscopy. To enable an in depth molecular analysis of the chromatin landscape and gene expression patterns, these markers will be utilised to isolate cell populations by FACS. This will require tagging these genes with fluorescent flags using CRISPR-Cas9 targeting – a method used routinely in the laboratory.

In the course of the work you will analyse the roles of Zic1 and Erf in the development of cranial sutures. Working with both embryonic and postnatal mutant and WT mice you will learn the histological and immunohistochemical approaches used to gain insight into pathological mechanisms. CRISPR-Cas9 targeting will be used to develop cell or mouse lines as an aid for visualising cellular and developmental pathology. These studies could be complemented by in vitro analysis of mesenchymal stem cells (MSC) isolated from the sutures of mutant and WT mice. Such studies will involve analysing the capacity of MSC to differentiate to bone, RNAseq to detect altered gene expression patterns, and ChIPseq to profile the DNA binding pattern of specific transcription factors.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford. Students are also able to attend the Methods and Techniques course run by the MRC Weatherall Institute of Molecular Medicine. This course runs through the year, ensuring that students have the opportunity to build a broad-based understanding of differing research techniques.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

The department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to support the careers of female students and staff.

Publications

1

Twigg SR, Vorgia E, McGowan SJ, Peraki I, Fenwick AL, Sharma VP, Allegra M, Zaragkoulias A, Sadighi Akha E, Knight SJ, Lord H, Lester T, Izatt L, Lampe AK, Mohammed SN, Stewart FJ, Verloes A, Wilson LC, Healy C, Sharpe PT, Hammond P, Hughes J, Taylor S, Johnson D, Wall SA, Mavrothalassitis G, Wilkie AO. 2013. Reduced dosage of ERF causes complex craniosynostosis in humans and mice and links ERK1/2 signaling to regulation of osteogenesis.Nat. Genet.,  45 (3), pp. 308-13.

2

Twigg SR, Wilkie AO. 2015. A Genetic-Pathophysiological Framework for Craniosynostosis.Am. J. Hum. Genet.,  97 (3), pp. 359-77.

3

Twigg SR, Forecki J, Goos JA, Richardson IC, Hoogeboom AJ, van den Ouweland AM, Swagemakers SM, Lequin MH, Van Antwerp D, McGowan SJ, Westbury I, Miller KA, Wall SA, WGS500 Consortium, van der Spek PJ, Mathijssen IM, Pauws E, Merzdorf CS, Wilkie AO. 2015. Gain-of-Function Mutations in ZIC1 Are Associated with Coronal Craniosynostosis and Learning Disability.Am. J. Hum. Genet.,  97 (3), pp. 378-88.

Research Themes, Tools and Technologies

Supervisors

Key Dates for October 2018 Entry

Application deadline:  12 noon GMT on Monday 8 January 2018

Interviews for shortlisted candidates: Week commencing Monday 22 January 

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How to apply

To apply for a place on the DPhil in Medical Sciences you will need to submit an application using the online application form.

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