DESCRIPTION (provided by applicant): In order to minimize and prevent craniofacial anomalies, it is essential to understand the specific cause of individual malformation syndromes. However, this requires a deep appreciation of the normal developmental events that shape head and facial development during embryogenesis. The majority of the tissues of the head and face including bone, cartilage, connective and peripheral nervous system tissue are derived from a cell population called the neural crest. Most craniofacial syndromes are thought to occur due to a defect in the neural crest cell development during embryogenesis. Thus it is essential to study how and when neural crest cells are formed, what guides neural crest cells to their final destinations, what keeps neural crest cells alive and also how neural crest cells decide to become cartilage or bone of connective and nerve tissue. In this proposal we study a mouse model of Treacher Collins syndrome, which replicates the severe craniofacial disorder in humans. Treacher Collins syndrome arises due to a developmental defect occurring during embryogenesis in which insufficient neural crest cells are generated to make a normal head and face. We have identified a broad mechanism by which we can prevent the development of craniofacial anomalies typical of Treacher Collins syndrome and in this proposal we refine this process to facilitate future clinical applications. In addition, since our mouse model of Treacher Collins syndrome represents one of few mouse animal models that exhibit a defect in neural crest cell formation, we have used this model to identify new genes that are important for neural crest cell and craniofacial development. For the purpose of this proposal we focus on one gene, called Nr6a1, which appears to be critical for the neural crest cell formation process and as such is essential for normal craniofacial development.

Craniofacial abnormalities account for approximately one third of all birth defects in new born kids, are a major cause of infant mortality and dramatically impact upon national health care budgets. Disorders such as Treacher Collins, Pierre Robin and Waardenburg syndromes, along with holoposencephaly and craniosynostosis to name a few, have serious lifetime functional, esthetic and social consequences that are devastating to children and parents alike. Comprehensive surgery, dental care, psychological counseling and rehabilitation help ameliorate the problems, but at a great cost over many years. The Center for Disease Control estimates that the lifetime cost of treating the children born each year with cleft lip and/or cleft palate alone to be $697 million. Post-natal treatment of malformation syndromes such as Treacher Collins through comprehensive, well-coordinated and integrated strategies can provide satisfactory management of each condition. However, the results are often variable and rarely fully corrective, hence considerable effort needs to be invested into developing therapeutic avenues of prevention. This can only come from a deep appreciation of the precise etiology and pathogenesis of individual malformation syndromes, which is built upon a thorough understanding of the normal events that regulate neural crest cell patterning and craniofacial development.