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Morphogens and Axons in the Regulation of Adult Neural Stem Cells


Neural stem cells (NSCs) persisting in the walls of the lateral ventricles of the adult mammalian brain continue to produce new neurons and glia throughout life. The identification of NSCs, and long-range migration and integration of new neurons and glia into fully developed neural circuits suggest possible strategies for brain repair. Understanding the mechanisms that regulate adult neurogenesis will better enable us to harness the regenerative potential of NSCs for neuronal replacement. In this dissertation, I demonstrate an extensive plexus of supraependymal serotonergic (5HT) axons. These 5HT axons form intimate contacts with the apical domain of NSCs and likely regulate their proliferation via the 5HT2C receptor. Also on the apical domain of NSCs is a small, highly specialized organelle called the primary cilium, known for its role in signal transduction, but whose function in adult NSCs is unknown. I show that primary cilia are required for a unique population of progenitors in the ventral region of the ventricular-subventricular zone (V-SVZ), and that ablation of primary cilia disrupts Sonic hedgehog (Shh) signaling in these progenitors. Further, I identify a novel Shh-dependent domain in the dorsal V-SVZ, which generates not only olfactory bulb (OB) neurons, but also astrocytes and oligodendrocytes that migrate to the cortex and corpus callosum (CC). These new findings expand our knowledge on the endogenous mechanisms that control the NSC niche in the adult mammalian brain.

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