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.
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.
|Adlaf, Elena W; Mitchell-Dick, Aaron; Kuo, Chay T (2016) Discerning Neurogenic vs. Non-Neurogenic Postnatal Lateral Ventricular Astrocytes via Activity-Dependent Input. Front Neurosci 10:111|
|Dieni, Cristina V; Panichi, Roberto; Aimone, James B et al. (2016) Low excitatory innervation balances high intrinsic excitability of immature dentate neurons. Nat Commun 7:11313|
|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 ChATâº neurons and activity-dependent control of postnatal SVZ neurogenesis. Nat Neurosci 17:934-42|
|Wang, Wenbin; Pan, Yung-Wei; Wietecha, Tomasz et al. (2013) Extracellular signal-regulated kinase 5 (ERK5) mediates prolactin-stimulated adult neurogenesis in the subventricular zone and olfactory bulb. J Biol Chem 288:2623-31|
|Benner, Eric J; Luciano, Dominic; Jo, Rebecca et al. (2013) Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4. Nature 497:369-73|
|Pan, Yung-Wei; Kuo, Chay T; Storm, Daniel R et al. (2012) Inducible and targeted deletion of the ERK5 MAP kinase in adult neurogenic regions impairs adult neurogenesis in the olfactory bulb and several forms of olfactory behavior. PLoS One 7:e49622|
|Pan, Yung-Wei; Chan, Guy C K; Kuo, Chay T et al. (2012) Inhibition of adult neurogenesis by inducible and targeted deletion of ERK5 mitogen-activated protein kinase specifically in adult neurogenic regions impairs contextual fear extinction and remote fear memory. J Neurosci 32:6444-55|
|Pan, Yung-Wei; Zou, Junhui; Wang, Wenbin et al. (2012) Inducible and conditional deletion of extracellular signal-regulated kinase 5 disrupts adult hippocampal neurogenesis. J Biol Chem 287:23306-17|
|Paez-Gonzalez, Patricia; Abdi, Khadar; Luciano, Dominic et al. (2011) Ank3-dependent SVZ niche assembly is required for the continued production of new neurons. Neuron 71:61-75|