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正确决定细胞命运是一个重要的问题。 发育生物学和再生医学的基本问题。颅神经嵴细胞 是一个很好的例子，一个明确的细胞谱系过渡，其中多能细胞通过一个步骤， 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以及颅面软骨和骨。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， 以及细胞如何被重新编程。我们假设cNCC软骨/神经元/神经胶质祖细胞 在整个发育过程中保持可塑性，cNCC命运的获得受以下调节的控制： 通过prdm 3的染色质可及性。拟议研究的理由是，深入了解 参与cNCC谱系转换的特定因素将为正常发育和 cNCC的可塑性以及祖细胞如何重新编程用于组织修复。我们将测试这个 1）检验prdm 3作为分子细胞命运的假说 在cNCC分化期间切换。在这里，我们将测试prdm 3活性在cNCC中是必需的这一假设。 通过抑制神经元细胞自主地促进祖细胞向软骨的临时募集 命运2)测试软骨/神经元/神经胶质（CNG）祖细胞通过以下方式保持可塑性的假设： 发育时间，并可以通过prdm 3的丢失重新编程。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， prdm 3. 3)检验Prdm 3通过控制以下因素来调节cNCC分化的时间的假设： 基因组可及性在目标3中，我们将检验Prdm 3的缺失会导致细胞中的整体改变的假设。 在cNCC祖基因的染色质状态，这反过来控制分化的时机。所有这些 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。 cNCC的可塑性，使得组织重编程可以被开发用于修复受损的颅面 组织中

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.