The role of epigenetic modifiers in regulating the developmental plasticity of cranial neural crest cells

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Summary How stem progenitor cells maintain plasticity for proper cell fate determination over developmental time is a fundamental question in developmental biology and regenerative medicine. Cranial neural crest cells (cNCCs) are an excellent example of a well defined cellular lineage transition in which multipotent cells step through a series of more restricted progenitors to give rise to diverse array of differentiated cell types, including neurons and glia of the peripheral nervous system as well as craniofacial cartilage and bone. Thus, understanding the genetic and epigenetic regulators in cNCC development is key to understanding how cell fate is determined as well as how cells can be reprogrammed. We hypothesize that the cNCC cartilage/neuron/glial progenitor retains plasticity through developmental time and cNCC fate acquisition is controlled by regulation of chromatin accessibility by prdm3. The rationale for the proposed studies is that an in-depth understanding of the specific factors involved in cNCC lineage transitions will provide insights into both normal developmental plasticity of cNCCs as well as how progenitors can be reprogramed for tissue repair. We will test this hypothesis in the following specific aims: 1) Test the hypothesis that prdm3 acts as a molecular cell fate switch during cNCC differentiation. Here we will test the hypothesis that prdm3 activity is required in cNCCs cell autonomously to promote the temporal recruitment of progenitors to cartilage by repressing neuronal cell fate. 2) Test the hypothesis that the cartilage/neuronal/glial (CNG) progenitor retains plasticity through developmental time and can be reprogramed by loss of prdm3. In Aim 2, hypothesis that CNG progenitors retain plasticity over developmental time and into larval stages and are reprogramed with loss of prdm3. 3) Test the hypothesis that Prdm3 regulates the timing of cNCC differentiation by controlling of genomic accessibility. In Aim 3, we will test the hypothesis that loss of Prdm3 leads to global alterations in chromatin state at cNCC progenitor genes, which in turn controls the timing of differentiation. 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 normal developmental plasticity of cNCCs such that tissue reprograming can be developed for the repair of damaged craniofacial tissues.