Post-transcriptional regulation of signaling systems during neural crest induction

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PROJECT SUMMARY/ABSTRACT The neural crest is a multipotent embryonic stem cell population that gives rise to most of the craniofacial skeleton including cartilage and bone. Misregulation of neural crest development results in several craniofacial anomalies and birth defects. Thus, elaboration of the processes guiding neural crest formation is imperative for diagnosis and treatment of pathologies associated with this cell type. Neural crest cells are induced by the combined action of signaling systems at the neural plate border, a stripe of progenitor cells adjacent to the neural plate. Opposing morphogen gradients of Wnts and FGFs are central for progenitor cells to decide between these two fates: induction of the neural crest requires high levels of Wnts and low levels of FGFs, while high levels of FGFs drive cells towards a neural fate. Recent studies highlight the requirement of a precise combination of signals for neural plate border induction, but we still have a superficial understanding for how levels of FGF and Wnt are fine-tuned to jumpstart the neural crest genetic program. A regulatory mechanism that may play a central role in tittering the activity of signaling pathways during early embryonic development is microRNA (miRNA) mediated gene silencing.4 Intriguingly, we found that inactivation of the miRNA pathway via knockdown of Dicer in avian embryos results in expansion of the neural plate territory at the expense of neural crest cells. Furthermore, we have recently employed small RNA-sequencing to identify miRNAs enriched in the neural crest. Our preliminary analysis of this dataset has indicated that neural crest miRNAs (i) are regulated by canonical Wnt signaling and that (ii) they target important components of the FGF signaling pathway. Accordingly, we hypothesize that Wnt signaling activates the expression of a set of miRNAs that inhibit FGF signaling to promote neural crest formation. To test our model, we will use genomic, functional, and biochemical approaches to define the regulation and function of Wnt-activated miRNAs in the neural crest. Our results will identify a novel post-transcriptional mechanism that acts downstream of signaling systems to regulate cell state transitions and will shed light on the molecular control of early craniofacial development.