A Tfap2-mediated molecular switch for neural crest induction and specification

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PROJECT SUMMARY/ABSTRACT The neural crest is a multipotent embryonic cell population that gives rise to most of the craniofacial skeleton, including cartilage, bone and connective tissue. Misregulation of neural crest development results in the vast majority of the craniofacial malformations and birth defects. Thus, uncovering the molecular and genetic underpinnings of neural crest formation has important implications for the diagnosis and treatment of these pathologies. Formation of the neural crest is a multistep process. This process begins with the induction of the neural plate border, which is a territory of cells that contains precursors of the neural crest, sensory placodes and central nervous system. Subsequently, during the process of specification, a subset of the cells from the neural plate border starts to express a combination of genes that is unique to bona fide neural crest cells. Several transcription factors are used reiteratively during neural crest formation; however, how they are able perform distinct functions during induction vs. specification is still unclear. One such factor, Tfap2a, has been shown to have crucial roles in both steps neural crest formation. Tfap2a belongs to the Tfap2 transcription factor family, consisting of paralogous proteins that may act as homo- or heterodimers to regulate gene expression. Two other Tfap2 paralogs, Tfap2c and Tfap2b, are co-expressed with Tfap2a at discrete stages of neural crest formation, during induction and specification, respectively. Preliminary data suggests that these factors are able to heterodimerize and regulate distinct groups of target genes. We hypothesize that Tfap2 heterodimers are part of a molecular switch to control the transition from induction to specification during neural crest development. First, Tfap2a cooperates with Tfap2c to mediate the induction of the neural plate border. Second, Tfap2a switches partners to heterodimerize with Tfap2b and drive expression of bona fide neural crest genes in a subset of cells within the neural plate border. We will test this model by employing stage-specific perturbation assays and identifying protein-DNA and protein-protein interactions in developing avian embryos. Our results will clarify how neural crest identity is progressively defined during development and shed light on how factors are able to perform distinct functions in different biological contexts throughout embryonic development.