Protein /Nucleic Acid Interactions In Embryogenesis

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In vertebrates, the ectoderm is subdivided during gastrulation into four primary fates: epidermis and central nervous system (CNS) on the ventral and dorsal surfaces, respectively, and neural crest and sensory placodes located between these two domains. The goal of this project is to understand the mechanisms that determine how ectodermal cells choose between these pathways, and how the ensuing tissue patterning and differentiation are regulated. The experimental approach taken by this laboratory has been to use dependence upon cell-cell signaling as a criterion for identifying genes that may regulate the ectodermal developmental programs. Attention has been focused on the transcriptional activator AP-2alpha. Neural crest induction in Xenopus requires two signals, a partially attenuated BMP signal and a Wnt/beta catenin signal. We have found that AP2alpha is responsible for conveying the BMP signal to the genome, and activation of a broad spectrum of neural crest-specific genes. AP2alpha is also critical in the development of epidermis. We used a hormone-inducible version of AP2alpha as a tool in conjunction with microarray analysis to identifiy target genes in both epidermis and neural crest. Approximately 100 such genes have now been identified, many of which have known functions such as transcription factors, signaling molecules, extracellular matrix-related enzymes and other structural or enzymatic functions. Many also have no known function, but are conserved in the mouse and human genomes and are thus likely to be important. We are now focusing our research on determining the function of a small number of these genes. In particular, we are interested in two; one is a gene we named "Inca" (for Induced in Neural Crest by AP2). Inca is conserved in sequence and expression pattern in frogs, mice, and zebrafish. In the frog, Inca is required for proper development of the craniofacial cartilage and bones, the intestines, and other tissues where neural crest is involved. Another gene encodes an adhesion molecule that is transiently expressed in neural crest and developing somites. In addition we are continuing to study the AP2 family of transcription factors and their role in ectodermal development. Since these genes are conserved throughout vertebrate phylogeny, our findings should have broad relevance to biomedical research and human health and development.