Building the skull - normal and abnormal development

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This project will focus on craniosynostosis, the premature fusion of one or more sutures separating the bones of the skull vault. A complex network of developmental mechanisms is involved in patterning and maintaining this complex system of bones, and a variety of genetic mutations can affect these processes to cause serious skull malformations. Oxford is a leading national referral centre in the surgical treatment of these malformations, enabling us study the entire process by which these arise from patient to mutation, and from mouse model to molecular pathogenesis.The project will exploit the large number of clinical samples available to explore specific hypotheses of causation. An early focus will involve investigation of the gene RUNX2, which encodes a master transcriptional regulator of ossification. There is likely to be the opportunity to interrogate whole genome sequence as part of the research programme of the new NHS Genomic Medicine Service diagnostics service. Potential epigenetic mechanisms of pathogenesis will be explored as well. To investigate pathophysiology, carefully selected mutations will be modelled in mice. We still know very little about what happens biologically in the cranial sutures themselves: these structures 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. We explore how the suture works by mapping out the cellular hierarchy of activities from undifferentiated stem cell to fully formed osteoblast, comparing results between normal sutures and those from mice with targeted mutations. A specific focus will be to elucidate the pathogenic mechanisms by which craniosynostosis arises in a Zic1-mutated mouse, available in the laboratory. The opportunity to generate additional targeted mouse mutants using CRISPR/Cas9 genome editing may arise out of the human genetics investigations.Specific skills acquired will include: (i) use of web resources to interpret genomic information from human, mouse and other species; (ii) experimental techniques including cell culture, fluorescence-activated cell sorting (FACS), microscopy, single cell transcriptomics and next generation sequencing, in addition to basic molecular biology methodologies; (iii) training in husbandry and phenotypic analysis of mice, with acquisition of a personal license and (iv) bioinformatics approaches to analysis of large datasets including genome sequencing, single cell transcriptomics, or epigenomics (full support will be available through the Centre for Computational Biology). Additional generic and transferable skills training will be provided through the MRC-WIMM DPhil Course and the Medical Sciences Division's Skills Training Programme.