Ependymal control of new neuron production in the adult brain

描述（由申请人提供）：在整个胚胎和出生后发育过程中，神经祖细胞/干细胞产生分化的神经元、星形胶质细胞和少突胶质细胞。虽然这些祖细胞在胚胎发育期间相对丰富，但它们被限制在成人大脑的特定区域。成年小鼠脑室下区（SVZ）神经源性生态位，容纳成体神经干细胞，由多睫状体室管膜细胞排列成针轴状结构，围绕心室表面单睫状体干细胞。这种生态位排列的功能意义尚不清楚，因为调节SVZ持续产生新神经元的分子机制尚不清楚。利用诱导小鼠遗传学、蛋白质生物化学和多光子实时成像的结合，我们计划验证室管膜细胞可能在控制成人大脑干细胞产生新神经元方面发挥关键作用的有趣假设。我们的初步结果表明，SVZ室管膜组织的诱导破坏导致成人神经发生的急剧减少。我们计划通过测试以下三个假设来探索这一观察结果：1)适配器蛋白锚蛋白3在维持成人SVZ神经发生中起关键作用；2) SVZ室管膜组织是维持B型星形胶质细胞神经发生潜能的特化信号中枢；3)神经源性SVZ B型星形细胞的分化受Foxj1+ SVZ小众祖细胞的调控。我们的研究旨在探索室管膜生态位组织、稳定性和新神经元产生之间的直接联系。为了使这个研究问题易于处理，我们开发了一种新的实时成像平台，使用多光子显微镜，一种新的初级室管膜培养试验，以及新的小鼠试剂来解决这些问题。我们的方法来理解新神经元是如何在成人大脑中持续产生的，应该具有广泛的适用性。SVZ神经干细胞及其后代被认为参与损伤后的大脑重塑。因此，解决控制新神经元产生的基本细胞机制，以及它们的室管膜邻居在这一过程中所起的关键作用，不仅可以进一步加深我们对成人神经发生的理解，而且有助于实现使用干细胞作为治疗剂的最终目标。

DESCRIPTION (provided by applicant): Throughout embryonic and postnatal development, neural progenitors/stem cells give rise to differentiated neurons, astrocytes, and oligodendrocytes. While these progenitors are relatively abundant during embryogenesis, they become restricted to specialized regions in the adult brain. The adult mouse subventricular zone (SVZ) neurogenic niche, housing adult neural stem cells, consists of multiciliated ependymal cells arranged in pinwheel-like structures around monociliated stem cells at the ventricular surface. The functional significance of this niche arrangement is unclear, as molecular mechanisms regulating the continued production of new neurons from the SVZ remain unknown. Using a combination of inducible mouse genetics, protein biochemistry, and multiphoton live-imaging, we plan to test the intriguing hypothesis that ependymal cells may hold a key role in controlling new neuron production from stem cells in the adult brain. Our preliminary results showed that inducible disruption of SVZ ependymal organization resulted in dramatic reduction of adult neurogenesis. We plan to explore this observation by testing the following three hypotheses: 1) the adapter protein Ankyrin 3 plays a critical role in sustaining adult SVZ neurogenesis; 2) SVZ ependymal organization serves as specialized signaling hubs to retain neurogenic potential of type B astrocytes; and 3) differentiation of neurogenic SVZ type B astrocytes is controlled by Foxj1+ SVZ niche progenitors. Our study proposes to explore a direct connection between ependymal niche organization, stability, and production of new neurons. To make this research question tractable, we have developed a novel live-imaging platform using multiphoton microscopy, a new primary ependymal culture assay, as well as new mouse reagents to address these problems. Our approaches to understand how new neuron production is sustained in the adult brain should have wide applicability. SVZ neural stem cells and their progeny are thought to participate in brain remodeling after injuries. Therefore, tacklin the basic cellular mechanisms controlling their generation of new neurons, and the key roles played by their ependymal neighbors in this process, should further not only our understanding of adult neurogenesis, but will also help in accomplishing the eventual goal of using stem cells as therapeutic agents.