Transcription factor activator protein 2 in development and disease of the neural crest

The neural crest (NC) is a vertebrate specific early embryonic stem-cell population that forms an array of derivatives in the developing embryo. These cells are induced from the developing ectoderm at the boundary of the neural plate and non-neural ectoderm (termed the neural plate border). After initial induction the NC migrate along predefined routes within the developing embryo and upon reaching their destination begin to differentiate into this myriad of derivatives. These derivatives include neurons, glia, cartilage, bone, connective tissue and pigmented melanocytes, among others. Through genetic studies a variety of genes important in these various stages of NC development have been identified. Together, these genes comprise the emerging NC gene-regulatory-network (NC-GRN). Although a variety of genetic components have been identified exactly how they interact with one another during NC development is not fully understood. One key family of genes important in the NC-GRN is the transcription factor activator protein 2 (TFAP2). Initial studies had identified an important role for TFAP2 in initial NC induction, as elimination of two family members (TFAP2A and TFAP2C) resulted in a complete absence of NC and all subsequent derivatives. Although TFAP2 was critical for NC development it was not clear exactly how TFAP2 fit into the NC-GRN and whether additional roles of TFAP2 existed within this network. Here in, we have addressed these questions by identifying a key transcriptional target of TFAP2, SOX10, during NC development. In addition, we have examined how TFAP2 is regulated by Wnt-signaling during NC development. Finally, we have identified an additional role for TFAP2 family members in regulating an additional step of NC development mainly the differentiation of NC-derived melanocytes and identified several targets that may mediate this effect. Together these findings provide a more clear understanding of TFAP2's role in the NC-GRN during development. Given disruption of this network contributes to disease of the NC these findings should provide insight into the etiology as well as provide potential therapeutic intervention for these diseases. In addition, understanding differences in the vertebrate NC-GRN to non-vertebrate GRN's should provide insight into the emergence of this important cell type during evolution.