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Unraveling the aetiology of human craniofacial disorders using multidisciplinary approaches

   Faculty of Biology, Medicine and Health

About the Project

Craniofacial anomalies constitute an estimated 35% of all birth defects, yet only a fraction of the underlying causes are known. Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder involving first and second branchial arch derivatives, characterised by ear anomalies, hemifacial microsomia, vertebral malformations and ocular defects. It affects ~1:5600 live births and is the 4th most common craniofacial birth defect, with a significant associated health burden on patients, and health-care costs for society. A genetic basis is implicated in ~4% of cases, however the genetic aetiology in most cases is unknown making accurate diagnosis and management difficult.

Retinoic acid (RA) (active metabolite of vitamin A) is essential for normal development, and slight changes in RA signaling dynamics results in abnormal craniofacial morphology. Exposure to excess exogenous RA is an established cause of first arch malformations, and our findings of mutations in a key cellular RA catabolising enzyme, CYP26A1, shows that dysregulation of RA signaling may underlie the disorder more generally. RA signalling also modulates Notch signalling but the mechanism is poorly understood. The Notch signalling pathway is involved in a host of activities including neural development, somatogenesis and regeneration, as well as osteogenic differentiation and the development of the skeleton. We are therefore interested in understanding neural crest (NC) development related to Notch signalling. It is known that downstream targets of Notch signaling such as the her/hes family are expressed in the NC. The her/hes gene family are well known neural progenitor (NP) markers and we want to get a better understanding of how misregulation of RA levels by Cyp26a1 affects Notch signalling, and ultimately determine the effect on NP cells. We have generated a cyp26a1 knockout model to investigate this. Altogether, this will help us understand how dysregulation of RA results in the craniofacial abnormalities seen in patients.

Disorders such as OAVS are heterogeneous and multidisciplinary approaches are needed to identify all the genes involved and unravel the underlying pathomechanisms. This project will utilize large scale exome/genome sequencing of carefully phenotypes patient cohorts, alongside functional and in vivo models to achieve this aim. The crucial role that the retinoic acid signaling pathway and associated gene networks play in craniofacial development and human conditions such as OAVS will also be an important avenue to explore.

Entry Requirements

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. Candidates with experience in molecular biology and working with zebrafish models or with an interest in bioinformatics and genome screening are encouraged to apply.

How To Apply

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website ( Informal enquiries may be made directly to the primary supervisor. On the online application form select the appropriate subject title.

For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences.

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website”

For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit

Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website).


1. Beleza-Meireles A, Clayton-Smith J, Saraiva JM, Tassabehji M. Oculo-auriculo-vertebral spectrum: a review of the literature and genetic update. J Med Genet. 2014 Aug 12. pii: jmedgenet-2014-102476.

2. Beleza-Meireles A, Hart R, Clayton-Smith J, Oliveira R, Reis CF, Venâncio M, Ramos F, Sá J, Ramos L, Cunha E, Pires LM, Carreira IM, Scholey R, Wright R, Urquhart JE, Briggs TA, Kerr B, Kingston H, Metcalfe K, Donnai D, Newman WG, Saraiva JM, Tassabehji M. Oculo-auriculo-vertebral spectrum: Clinical and molecular analysis of 51 patients. Eur J Med Genet. 2015 Sep;58(9):455-65.

3. Li, N., et al., Regulation of neural crest cell fate by the retinoic acid and Pparg signalling pathways. Development, 2010. 137(3): p. 389-94.

4. Lopez, E., et al., Mutations in MYT1, encoding the myelin transcription factor 1, are a rare cause of OAVS. J Med Genet doi:10.1136/jmedgenet-2016-103774
Notch3 activation is sufficient but not required for inducing human T-lineage specification.

5. Waegemans E, Van de Walle I, De Medts J, De Smedt M, Kerre T, Vandekerckhove B, Leclercq G, Wang T, Plum J, Taghon T.J Immunol. 2014 Dec 15;193(12):5997-6004. doi: 10.4049/jimmunol.1400764. Epub 2014 Nov 7.PMID: 25381438

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