Ependymal control of new neuron production in the adult brain

点击翻译按钮获取中文摘要

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.