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

总结 干祖细胞如何在发育过程中保持可塑性以决定正确的细胞命运是一个研究课题 发育生物学和再生医学的基本问题。颅神经嵴细胞 (cNCC) 是明确的细胞谱系转变的一个很好的例子，其中多能细胞逐步经历 一系列更受限制的祖细胞产生多种分化细胞类型，包括神经元 和周围神经系统的神经胶质细胞以及颅面软骨和骨骼。因此，了解 cNCC 发育中的遗传和表观遗传调节因子是理解细胞命运如何决定的关键 以及细胞如何重新编程。我们假设 cNCC 软骨/神经元/神经胶质祖细胞 通过发育时间保留可塑性，并且 cNCC 命运的获得受以下调节的控制： Prdm3 的染色质可及性。拟议研究的理由是深入了解 参与 cNCC 谱系转变的具体因素将提供对正常发育的见解 cNCC 的可塑性以及祖细胞如何重新编程以进行组织修复。我们将测试这个 假设的具体目标如下： 1）检验prdm3作为细胞命运分子的假设 cNCC 分化期间进行切换。在这里，我们将检验 cNCC 中需要 prdm3 活性的假设 细胞自主地通过抑制神经元细胞促进祖细胞暂时募集到软骨 命运。 2）检验软骨/神经元/神经胶质（CNG）祖细胞通过以下方式保留可塑性的假设： 发育时间，并且可以通过丢失prdm3而重新编程。在目标 2 中，假设 CNG 祖细胞在发育过程中保持可塑性并进入幼虫阶段，并在失去 prdm3。 3) 检验 Prdm3 通过控制 cNCC 分化时间的假设 基因组可及性。在目标 3 中，我们将检验 Prdm3 丢失导致全局改变的假设 cNCC 祖基因的染色质状态，进而控制分化的时间。在一起，这些 研究将揭示 cNCC 在发育过程中如何分化为特定细胞类型的基本信息。 该提案的结果有可能揭示有关正常发育的重要新见解 cNCC 的可塑性，可以开发组织重编程来修复受损的颅面 组织。

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.