The role of Foxd3 in neural crest stem cell function

描述（由申请人提供）：干细胞代表了一种独特的细胞类型，具有疾病治疗的潜力。然而，为了利用这种生物学潜力，我们必须了解控制祖细胞的特化、维持和分化的遗传途径。我们的实验室已经确定了一个转录因子，Foxd 3，在一些胚胎祖细胞谱系和神经嵴细胞中表达。也许更重要的是，Foxd 3的功能（体内和体外），以维持干/祖细胞在未分化状态，因为他们继续增殖。小鼠中转录因子Foxd 3的神经嵴特异性缺失证明了在神经嵴维持的早期事件中对Foxd 3的深刻需求。几乎所有的神经嵴谱系都受到Foxd 3缺失的不利影响，这支持了Foxd 3功能是维持神经嵴的多能干细胞特性所必需的假设。关键调控基因如Foxd 3的鉴定是利用体外和最终体内多能性操纵以实现治疗目标的潜力的重要的第一步。在本提案中，我们将重点关注Foxd 3在体外和体内维持多能性中的功能：在目的1中，我们将改进体外神经嵴干细胞的分析和从这些祖细胞中删除Foxd 3的结果，关于自我更新和多能性，在目的2中，我们将在体内评估迷走神经嵴群的神经和神经胶质分化，以精确定义Foxd 3在其中起作用的神经嵴亚群。这些实验都集中在了解这些神经嵴祖细胞分化的调节。NINDS的使命是减轻神经系统疾病的负担，神经干细胞疗法是治疗这些疾病的一种可能的未来方法。了解控制神经发育的分子将推动该领域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了解调节神经嵴干/祖细胞的分子机制，并最终了解神经嵴祖细胞亚群的分子调节的异同。在这里获得的知识可以直接应用于其他干细胞祖细胞，并将导致更好地了解如何操纵干细胞的命运，以帮助促进干细胞为基础的治疗在未来。

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.