Grant: Operating Grant

This proposal is aimed at understanding the molecular pathways that coordinate the growth and development of the skull. Defects in the formation of the skull account for a large number of congenital malformations (i.e. present at birth) in Canadian children. Development of the skull is a complex process. Growth of the skull (or cranium) must occur in concert with the growth of the brain. As the brain rapidly increases in size early in postnatal development, the skull must remain plastic to accommodate these changes. Such plasticity is achieved by cranial sutures, which are fibrous joints that form at the interface of opposing cranial bones. These sutures remain unfused during early childhood in what is commonly referred to as the "soft spot" of the skull. The premature fusion of the cranial sutures causes craniosynostosis and occurs at a frequency of 1 in 2500 live births. Unless surgically treated, this disorder can impede brain growth and impair a child's intellectual development. The molecular and cellular mechanisms that regulate cranial growth are poorly understood. The gene FOXC1 is essential for normal craniofacial(i.e. skull and face) development in humans and mice. We will utilize genetic and biochemical approaches to dissect the role of FOXC1 in the formation of the skull. These experiments will improve our understanding of the regulatory mechanisms that control cranial bone formation. Such research will be instrumental in understanding how dysregulation of developmental pathways contribute to the pathologies of craniofacial malformations. Furthermore, these studies are essential if we wish develop safer and more effective means to treat craniofacial malformations.