Book Description

Understanding how cell fate decisions are regulated by signaling pathways and transcription factors is key to understanding how embryonic development takes place. Neural crest cells are an embryonic cell type that must undergo several cell fate choices and changes in gene expression before they are able to finally differentiate and contribute to adult tissues. Neural crest cells are formed at the border between developing neural and non-neural ectoderm in a region called the neural plate border. They are induced by several signaling factors and specified by the expression of transcription factors which will form a gene regulatory network for their development and control subsequent programs within the neural crest cells such as epithelial-to-mesenchymal transition, migration, and differentiation, which are required for proper development of the embryo. One transcription factor that is required for neural crest specification is the PR/SET domain containing transcription factor Prdm1a. The goal of this thesis is to explore the mechanisms by which Prdm1a regulates genes required for neural crest specification and migration. Prdm1a is expressed in the early neural plate border, and when its expression is abrogated, neural crest cells are significantly reduced. Here, I have demonstrated that Prdm1a is downstream of known signaling pathways that induce neural crest cells, specifically Wnt and Notch signaling. Prdm1a directly activates the expression of the neural crest specification genes foxd3 and tfap2a, which are also required for neural crest formation. In addition to its role as a transcriptional activator, Prdm1a is also required as a transcriptional repressor of yet unknown targets and this role is required for specified neural crest cells to continue development to migratory stages. Using whole-genome and transcriptome approaches, I was able to identify several novel targets of Prdm1a regulation, demonstrating its role as a master regulator of several genetic programs required for the formation of the neural crest and possibly other tissues as well including the neural plate and sensory placodes. Interestingly, one of the downstream targets of the Prdm1a regulatory network is a cell adhesion gene, cdon. I have demonstrated a novel role for cdon as a cell-autonomous regulator of neural crest motility and migration. Altogether, this work demonstrates the importance of the Prdm1a transcription factor and how Prdm1a and its downstream gene regulatory network influences and controls neural crest cell fate.