Craniofacial malformations constitute one of the major group of congenital defects in newborn human infants. The formation of the anterior aspect of the vertebrate embryo is a complex process for which we have few molecular details, especially regarding the contribution of the neural crest (NC). The neural crest is a transient structure composed of cells that migrate extensively throughout the embryo and contribute to a number of organs. The control of crest cell morphogenesis is critical to the embryo, in as much as abnormal neural crest migration or proliferation result sin a number of serious human disorders ranging from cleft palate, to frontonasal dysplasia. The cranial malformations observed in children exposed in utero to 13-cis retinoic acid (RA) or excess alcohol are a consequence of the drugs' effect on some aspect of crest cell morphogenesis. The long term goal of the laboratory is to define the factors controlling normal craniofacial development and to elucidate the mechanism and to elucidate the mechanism(s) by which retinoic acid (RA) and ethanol affect these processes. While other vertebrate systems have provided insight into some of the key steps in crest cell morphogenesis, these studies have been limited by the complexities of these organisms and inaccessibility of the embryonic tissues. We propose to use zebrafish as a model to study the role of the NC in craniofacial development. Since the embryo is transparent, the movement of individual cells can be visualized in real time. Like humans, the formation of the anterior structures of the zebrafish embryo is sensitive to teratogens like RA and ethanol. The studies outlined in this proposal focus on the transcription factor AP-2, which has been shown to be expressed in NC cell populations. Which make major contributions to the developing head in human, mouse and chick.
The specific aims of this proposal are: 1) To establish AP-2 as a marker for subsets of NC cells in zebrafish, and examine how exposure to RA and ethanol affect the morphogenesis of the AP-2+ crest cell populations; 2) To examine the role of AP-2 in craniofacial development by altering the expression of this gene product; 3) To follow the morphogenesis of AP-2+ cell populations in the living embryo. Through the use of this model system we will be able to gain significant insights into the dynamic movements of cranial NC cells during embryogenesis. These studies will have a major impact on our understanding of the hierarchy of cell movements and interactions critical for the normal formation of the head and facial structures.
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