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.

Public Health Relevance

Our nervous system is critically important for learning, memory, and our perception of the world around us. Injuries to the nervous system are not only often debilitating, but are difficult to treat since neurons do not regenerate themselves. Neural stem cells, which can continuously generate new neurons in the adult mammalian brain, hold promise as a form of replacement therapy for nervous system degeneration and injuries. The process regulating continued production of new neurons in the adult brain is poorly understood. This proposal examines the intriguing hypothesis that multiciliated ependymal cells that line the brain ventricles may hold the key to making new neurons in the adult brain. Our results will have important implications for adult neural stem cell function in health and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS078192-03
Application #
8624723
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Owens, David F
Project Start
2012-03-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
3
Fiscal Year
2014
Total Cost
$649,098
Indirect Cost
$235,660
Name
Duke University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Lyons, Gray R; Andersen, Ryan O; Abdi, Khadar et al. (2014) Cysteine proteinase-1 and cut protein isoform control dendritic innervation of two distinct sensory fields by a single neuron. Cell Rep 6:783-91
Paez-Gonzalez, Patricia; Asrican, Brent; Rodriguez, Erica et al. (2014) Identification of distinct ChAT? neurons and activity-dependent control of postnatal SVZ neurogenesis. Nat Neurosci 17:934-42