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

摘要 干祖细胞如何在发育过程中保持可塑性以决定适当的细胞命运 发育生物学和再生医学中的基本问题。脑神经脊细胞(CNCC) 是明确定义的细胞谱系转变的一个很好的例子，在这种转变中，多能细胞经历了 一系列更受限制的前体细胞，可产生包括神经元在内的各种分化细胞类型 周围神经系统以及头面部软骨和骨的神经胶质细胞。因此，理解 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 以及如何对细胞进行重新编程。我们推测CNCC软骨/神经元/神经胶质前体细胞 通过发育时间保持可塑性，CNCC命运获得受调控 染色质的可及性。建议进行研究的理由是，深入了解 涉及CNCC谱系转变的特定因素将提供对正常发育的洞察 CNCC的可塑性以及祖细胞如何被重新编程以用于组织修复。我们将对此进行测试 假设在以下特定目的：1)检验假设，即prdm3作为一个分子细胞命运 在CNCC分化过程中切换。在这里，我们将检验cNCC中需要prdm3活动的假设。 细胞自主性通过抑制神经细胞促进祖细胞向软骨的短暂募集 命运。2)验证软骨/神经元/神经胶质(CNG)前体细胞通过 发育时间，并可以通过失去Prdm3来重新编程。在目标2中，假设CNG 祖细胞在发育过程中保持可塑性，进入幼虫阶段，并在失去 Prdm3。3)检验Prdm3通过控制Pdm3调控CNCC分化时机的假设 基因组可及性。在目标3中，我们将检验这样一个假设，即Prdm3的丢失会导致全球变化 CNCC前体基因的染色质状态，进而控制分化的时间。加在一起，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。 这一提议的结果有可能揭示对正常发育的重要新见解。 CNCCs的可塑性，可用于修复颅面损伤的组织再编程 纸巾。

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.