Genetic and epigenetic regulation of cranial neural crest differentiation

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How cells become specified and differentiate at the correct time and place is a fundamental question in developmental biology. Cranial neural crest cells (cNCCs) are an excellent model system to understand this process due to the multipotent nature of the progenitor cells, generally unrestricted developmental potential with known lineage and derivatives, and defined gene regulatory networks. In addition to the gene networks, epigenetic regulators can affect the expression of numerous target genes and may help to explain the differences in penetrance and phenotype between individuals with the same genotype. This is important since defects in neural crest development underlie many human congenital birth defects, such as cleft lip with or without palate and many craniofacial syndromes. Thus, understanding the genetic and epigenetic regulators in cNCC development is key to understanding how cell fate is determined. We hypothesize that PRDM paralogs regulate global gene expression by regulating downstream targets oppositely, including Wnt pathway components, to control the timing of cartilage/bone differentiation within the cNCC lineage. The rationale for the proposed studies is that an in depth understanding of normal cNCC development will provide insights into normal biology and the etiology of neural crest-associated birth defects, many of which are thought to arise from cNCC abnormalities. We will test this hypothesis in the following specific aims: 1) Test the hypothesis that PRDM proteins act upstream of Wnt signaling to control the timing of cNCC differentiation into chondrocytes. We will test the hypothesis PROM paralog activity is required in cNCCs cell autonomously upstream of Wnt signaling to promote differentiation of chondrocytes. 2) Test the hypothesis that Prdm3 and Prdm16 genetically interact to regulate cNCC gene expression and chromatin accessibility. In Aim 2, hypothesis that Prdm3 and Prdm16 genetically interact to control gene expression via regulating transcription and chromatin modification specifically at cNCC and Wnt gene targets. 3) Test the hypothesis that Prdm3 regulates global gene expression by controlling the timing of genomic accessibility of Prdm16. In Aim 3, we will test the hypothesis that loss of Prdm3 leads to global alterations in chromatin state at cNCC progenitor genes via changes in binding of Prdm16 throughout the genome, which controls the liming of cNCC differentiation into chondrocytes. Together, these studies will reveal basic information of how cNCCs differentiate into specific cell types during development. The results of this proposal have the potential to reveal important new insights into cNCC development and how these processes go wrong in disease, with the hope of providing a foundation for the design of therapeutic strategies for neural crest associated birth defects.