Understanding the role of neural crest cells in congenital birth defects such as Treacher Collins Syndrome

Neural crest cells are a stem and progenitor cell population that gives rise to the majority of the bone, cartilage, connective and peripheral nerve tissues in the head and face. Not surprisingly, craniofacial anomalies which account for approximately one third of all congenital birth defects, arise largely through defects in neural crest cell patterning. Treacher Collins Syndrome is a rare human congenital disorder of craniofacial development which is characterised by numerous developmental anomalies including hypoplasia of the facial bones, middle and external ear defects and cleft palate. We have generated a mouse model of Treacher Collins Syndrome via null mutation of Tcof1 and through a combination of whole embryo culture together with cell lineage tracing and transplantations demonstrate that Tcof1 acts cell autonomously and that haploinsufficincy of Tcof1 induces massive neuroepithelial apoptosis. This in turn severely depletes the neural crest progenitor cell population, leading to insufficient numbers of migrating neural crest cells, which fail to proliferate appropriately and consequently results in hypoplasia of the cranioskeletal elements characteristic of Treacher Collins Syndrome. Tcof1 encodes a nucleolar protein known as treacle which is essential for normal ribosome biogenesis.