Protein/nucleic Acid Interactions In Vertebrate Embryogenesis

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The neural crest (NC) plays a critical role in the developmental of the vertebrate head, face and jaws, providing the bulk of the craniofacial skeleton as well as peripheral nervous system and other cranial tissues. Normal craniofacial development depends on proper induction, migration and differentiation of NC cells and derivatives. Deficiencies at any of these steps, whether due to intrinsic defects in NC itself, or in failure of NC cells to interact properly with adjacent tissues, can lead to birth defects: up to a third of all congenital malformations are craniofacial in nature and mostly due to such NC failures. We have used the frog Xenopus and the freshwater tropical fish Danio rerio(zebrafish)as experimental model organisms to study NC development. The starting point for this project was two transcription factors, TFAP2a and Dlx3, the regulation of which we showed several years ago to be critical for the early steps in NC development. We are now designing, establishing and using transgenic zebrafish lines expressing both wild-type and mutated versions of these factors, followed by morphological and gene expression analysis, to identify target genes for these factors, and also to study their function in later stages of neural crest migration and terminal differentiation. Our goal is to relate the regulation of specific genes by TFAP2 and Dlx factors to cranifacial development in human embryos, both normal and pathological, hoping to establish diagnostic tools and, eventually, therapeutic strategies for preventing and treating cranifacial dysmorphology, the most common form of birth defects in human infants.