RNA localization in neural crest migratory protrusions - SUMMARY A fundamental question in developmental biology is how migratory cells initiate migration, move in a directed fashion towards their target, terminate migration and differentiate. Neural crest cells (NCCs) are an excellent example of these developmental processes, initially forming at the neural plate border/dorsal neural tube, undergoing an epithelial to mesenchymal transition, and migrating before differentiating. This represents an important problem, because defects in neural crest development underlie many human congenital birth defects including Treacher-Collins syndrome, DiGeorge syndrome, and Hirschsprungs disease. We have determined that NCCs extend cell projections that are enriched in specific RNAs. From these data, we hypothesize that localization of specific migratory mRNAs to NCC protrusions by zipcodes are required for directed migration. The rationale for the proposed studies is that an in-depth understanding of the cellular mechanisms of normal NCC migration will provide insights into the etiology of both neural crest- associated birth defects, including numerous syndromes, and cancer cell metastasis. We will test this hypothesis in the following specific aims: 1) Test the hypothesis that specific mRNAs are enriched in NCC protrusions and are required for NCC migratory behavior. In Aim 1, we will determine the transcriptome and proteome of NCC projections and test their function. 2) Test the hypothesis that zipcode sequences in NCC protrusion localized mRNAs are required for localization and NCC migration. In Aim 2, we will examine the localization and function of UTR regulatory sequences. Together, these studies will reveal the cellular and molecular mechanisms by which specific RNAs and proteins enriched in NCC projections promote NCC migration. The results of this proposal have the potential to reveal important new insights into NCC migration in normal development and disease and will provide a foundation for the design of therapeutic strategies for neural crest associated birth defects.
