Craniofacial genetics

The craniofacial genetics research group is based within the Basic Sciences research theme.

Staff

About our research

Craniofacial anomalies are among the most common and distressing congenital malformations affecting humans. Research in our laboratory aims to understand the normal developmental mechanisms underlying craniofacial morphogenesis and how these are disturbed in a variety of birth defects.

Group research has identified genetic mutations underlying craniofacial malformations, including Treacher Collins syndrome, Van der Woude syndrome, amelogenesis imperfecta, and dentine dysplasia. These findings have contributed to quality-of-life improvements as they have impacted directly on clinical management of affected families by providing the basis for genetic counselling internationally.

Research has also provided unique insights into the pathogenesis of the above disorders. For example, it has established that the protein encoded by the Treacher Collins syndrome locus plays a central role in ribosomal DNA transcription and is a unique regulator of ribosome biogenesis, a deficiency of which results in neuroepithelial cell death and disruption of neural crest cell formation. The group has also demonstrated the potential therapeutic utility of this research by preventing Treacher Collins syndrome through P53 inhibition in mice.

Similarly, the group has built on the discovery that interferon regulatory factor 6 (IRF6) is the Van der Woude syndrome locus by demonstrating that 
this major cause of cleft lip and palate results from abnormalities in ectodermal development and establishing that IRF6 plays a key role in oral periderm formation, appropriate development of which prevents cleft palate.

Recently, the group used an animal model to demonstrate that a mutation in the amelogenin gene, analogous to those found in humans, underlies amelogenesis imperfecta in mice. Enamel mineral density analysis and microdissection of the developing enamel revealed severe defects of enamel biomineralisation. Histological, immunofluorescence and electron microscopy studies demonstrated loss of ameloblast phenotype and increased ameloblast apoptosis resulting from endoplasmic reticulum stress.

More recently the group is using systems-level strategies to delineate molecular regulatory networks in development of the lip and palate, and dissect how their modification is related to the pathogenesis of cleft lip and palate. The group is compiling a catalogue of gene activity in tissues dissected from normal and knockout mouse embryos at critical developmental stages during formation of the lip and palate using a combination of transcriptome sequencing (RNA-seq) and chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq) with antibodies that mark cis-regulatory elements and transcription factor binding, including p63 and Gli proteins.

In collaboration with colleagues, probabilistic modelling and statistical inference approaches are being used to delineate regulatory interactions within and between stages and tissues.

Current postgraduate research students

• Laura Vicario Rodriguez
• Robert Sullivan
• Nigel Hammond