Dr. Erwin Pauws, UCL Great Ormond Street Institute of Child Health, London
Tuesday 30th January, 1.00 p.m., Stacey Lecture Theatre 1
Collectively, around a third of all birth defects are craniofacial, with cleft lip and/or palate and craniosynostosis being the most common. Crouzon-Pfeiffer syndrome is characterised by craniosynostosis -premature fusion of the cranial sutures- which is often accompanied by cleft palate. Although mutations in the FGFR2 gene have been identified in patients, major questions remain unanswered about the molecular and developmental pathogenesis. In particular, it is still not known how uncontrolled FGF signalling leads to the skeletal defects that characterise this syndrome. Elucidating the complex nature of FGFR2 signalling during embryonic development will improve the understanding of normal craniofacial development and its related pathologies, while providing a framework for the development of novel therapeutic strategies.
Previous work in our laboratory has focussed on a mouse model for Crouzon syndrome that carries a missense mutation (p.C342Y) in the gene encoding FGFR2. We have found dysmorphology of cartilage and bone in the C342Y mutant skull, as well as craniosynostosis and cleft palate, mimicking the human condition. More recently we have studied a mouse model of transgenic Fgfr2 overexpression which results in craniofacial hypoplasia and cleft palate, but without craniosynostosis. Together, we have shown that these developmental defects are caused by aberrant RAS/ERK signalling downstream of the FGF receptor and that tissues originating from neural crest derived mesenchyme are the primary target. Furthermore, differentiation of osteoblast progenitors is affected by aberrant FGF signalling, causing a delay in osteoblast maturation. This explains the hypoplasia-related phenotypic features associated with craniofacial birth defects, but appears not to be essential to the pathogenesis of craniosynostosis. We hypothesize that sutural mesenchyme is formed using a different signalling pathway, related to its different embryonic origin.
Ultimately, our aim is to use the increased knowledge of the cellular and molecular pathogenesis of these birth effects to develop pharmacological, non-surgical therapy alternatives or adjuvants to reduce the clinical burden on patients and their families.