Regulation of Neurogenesis by Jagged1 in the Embryonic SVZ

描述(由申请人提供)：本提案的目的是研究Jagged1在胚胎晚期嗅觉系统的脑室下区(SVZ)神经发生中的作用。先前的研究表明，Jagged1基因的缺失会导致SVZ内细胞分裂的减少。然而，SVZ内哪些细胞类型会产生这种表型尚不清楚。在SVZ中，神经干细胞产生转送放大细胞，转而产生神经母细胞前体。我假设在神经发生过程中，Jagged1是这些转变中的一个或两个所必需的。我将使用Jagged1突变体和免疫组织化学方法来确定在神经发生过程中哪些细胞类型受到影响。已知Jagged1调节SVZ中的细胞分裂。然而，是什么机制控制着Jagged1的激活和表达？已有研究表明，Jagged1被癌细胞中的WNT信号激活。众所周知，WNT还可以调节大脑中的神经发生，但这个过程是如何发生的仍然知之甚少。我推测WNT通过控制SVZ中Jagged1的表达来调节神经发生。我将使用SVZ衍生的神经球和药理学方法来确定Jagged1是否介导WNT对神经发生的调节。 公共卫生相关性：脑室下区的神经发生在嗅觉学习和记忆中起着关键作用。在SVZ，在由缺血和中风触发的条件下，神经发生增加。因此，了解SVZ中神经发生的调控机制对许多健康影响是一个重要的过程。

DESCRIPTION (provided by applicant): The goal of this proposal is to investigate the role of Jagged1 during late embryonic neurogenesis in the subventricular zone (SVZ) of the olfactory system. Prior studies have shown that loss of Jagged1 leads to reduced cell division within the SVZ. However, what cell-types are affected within the SVZ to produce this phenotype is still unknown. In the SVZ, neural stem cells give rise to transit amplifying cells, which in turn produce neuroblast precursors. I hypothesize that Jagged1 is required for one or both of these transitions during neurogenesis. I will use Jagged1 mutants and immunohistochemical approaches to determine what cell types are affected during neurogenesis. Jagged1 is known to regulate cells division in the SVZ. However, what mechanisms control Jagged1 activation and expression? It has been shown that Jagged1 is activated by wnt signaling in cancer cells. Wnt is also known to regulate neurogenesis in the brain, but how this process occurs is still poorly understood. I hypothesize that wnt regulates neurogenesis by controlling Jagged1 expression in the SVZ. I will use SVZ-derived neurospheres and pharmacological approaches to determine if Jagged1 mediates wnt regulation of neurogenesis. PUBLIC HEALTH RELEVANCE: Neurogenesis in the subventricular zone plays a critical role in olfactory learning and memory. In the SVZ, neurogenesis increases under conditions that are triggered by ischemia and stroke. Therefore, understanding the mechanisms that regulate neurogenesis in the SVZ is an important process for many health implications.