The role of Foxd3 in neural crest stem cell function

描述(申请人提供)：干细胞是一种独特的细胞类型，具有治疗疾病的潜力。然而，为了利用这一生物学潜力，我们必须了解控制祖细胞的指定、维持和分化的遗传途径。我们的实验室已经鉴定出一种转录因子Foxd3，它在许多胚胎祖细胞系和神经脊细胞中表达。也许更重要的是，Foxd3在体内和体外的功能是维持干细胞/祖细胞在继续增殖时处于未分化状态。小鼠神经峰特异性转录因子Foxd3的缺失表明，在神经峰维持的早期事件中，对Foxd3有着深刻的需求。事实上，Foxd3的缺失对所有神经脊谱系都有不利影响，这支持了Foxd3功能是维持神经脊多能干细胞特性所必需的假说。识别关键的调控基因，如Foxd3，是在体外和最终在体内为治疗目标而操纵多能性的潜力的重要的第一步。在本提案中，我们将重点关注Foxd3在体外和体内维持多能性方面的功能：在目标1中，我们将完善体外对神经脊干细胞的分析以及从这些前体细胞中删除Foxd3的自我更新和多能性的结果；在目标2中，我们将评估体内迷走神经脊群的神经和神经胶质分化，以准确确定Foxd3在其中发挥作用的神经脊亚群。这些实验都是为了了解这些神经脊祖细胞分化的规律。NINDS的使命是减轻神经系统疾病的负担，神经干细胞疗法是这些疾病未来可能的一种方法。了解控制神经发育的分子将推动该领域的发展，使这些治疗成为现实。与公共卫生的相关性：这些目标的实现将有助于我们理解调控神经脊干/祖细胞的分子机制，并最终了解神经脊祖细胞亚群分子调控的异同。在这里获得的知识可以直接应用于其他干细胞前体，并将导致对如何操纵干细胞命运的更好理解，以帮助促进未来基于干细胞的治疗。

DESCRIPTION (provided by applicant): Stem cells represent a unique cell type with potential for disease therapy. However, in order to take advantage of this biological potential, we must understand the genetic pathways controlling specification, maintenance and differentiation of progenitor cells. Our laboratory has identified a transcription factor, Foxd3, expressed in a number of embryonic progenitor lineages and in neural crest cells. Perhaps more importantly, Foxd3 functions (both in vivo and in vitro) to maintain stem/progenitor cells in an undifferentiated state as they continue to proliferate. Neural crest-specific deletion of the transcription factor Foxd3 in mice demonstrates a profound requirement for Foxd3 in early events of neural crest maintenance. Virtually all neural crest lineages are adversely affected by the loss of Foxd3, supporting the hypothesis that Foxd3 function is required for maintenance of multipotent stem cell properties of neural crest. Identification of key regulatory genes such as Foxd3 is an important first step in exploiting the potential for manipulation of multipotency in vitro and eventually in vivo for therapeutic goals. In this proposal we will focus on the function of Foxd3 in the maintenance of multipotency in vitro and in vivo: in Aim 1, we will refine the analysis of neural crest stem cells in vitro and the results of deleting Foxd3 from these progenitors with respect to self-renewal and multipotency, and in Aim 2, we will assess neural and glial differentiation of vagal neural crest populations in vivo to precisely define subpopulations of neural crest in which Foxd3 is functioning. These experiments are all focused on understanding the regulation of differentiation of these neural crest progenitors. The mission of the NINDS is to reduce the burden of neurological disease, and neural stem cell therapies are one possible future approach for these diseases. Understanding the molecules controlling neural development will advance the field toward making these treatments a reality. Relevance to Public Health: Accomplishment of these aims will help us to understand the molecular mechanisms regulating neural crest stem/progenitor cells, and eventually, similarities and differences in the molecular regulation of subsets of neural crest progenitors. Knowledge gained here can be directly applied to other stem cell progenitors and will lead to a better understanding of how to manipulate stem cell fate to help facilitate stem cell based therapies in the future.