Neural stem cells (NSCs) in the ventricular-subventricular zone (V-SVZ), an extensive germinal zone lining the walls of the lateral ventricles, continue to produce neurons and oligodendrocytes throughout juvenile and adult life (Ming and Song, 2011;Ihrie and Alvarez-Buylla, 2011). Identification of the NSCs, their progeny, and the mechanisms of adult neurogenesis, provide basic insight into brain repair and cancer (Sohur et al., 2006, Ma et al., 2009;Jacques et al., 2010). NSCs correspond to a subpopulation of V-SVZ astrocytes called B1 cells which generate specific types of neurons depending on their localization in different V-SVZ domains along the rostro-caudal and dorso-ventral axes. NSCs correspond to a subpopulation of V-SVZ astrocytes (B1 cells). B1 cells in different V-SVZ domains along the rostro-caudal and dorso-ventral axes generate specific types of neurons. Lineage expansion occurs through intermediate progenitors (C cells) and neuroblasts ( A cells) (Lois et al., 1996;Luskin et al., 1997;Doetsch et al., 1999b;Ponti et al. 2013a) and in rodents results in the generation of large numbers of new neurons that migrate to the olfactory bulb (OB) (Lois et al., 1994). In the infant human brain, V-SVZ-derived neurons not only migrate to the OB, but also into the cortex (Sanai et al.). The mode of division of B1 cells, the cell-cell interactions that occur during their division, and whether B1 cells self-renew - or ae consumed with age - is not known. The lineages of individual adult NSCs, whether they generate both neurons and glia, and which domains of the V-SVZ generate oligodendrocytes is also unknown. To address these questions, we have developed and validated a live-imaging method to directly visualize the behaviors of B1 and C cells within their niche and we have adapted and tested a barcode- retroviral lineage tracing method to investigate lineage relationships of cells derived from B1 cells in vivo.
Aim 1 will determine whether B1 cells self-renew and whether they divide symmetrically or asymmetrically, and will study their interaction with other cells in the V-SVZ.
In Aim 2 we present preliminary evidence of a transient postnatal (P0-P7) dorsal domain of the V-SVZ that is regulated by Sonic Hedgehog (Shh);initial observations indicate that this V-SVZ domain is an important source of oligodendrocytes in addition to neurons. We will examine whether single B1 cells in this domain are multipotent, and will analyze the function of Shh in the regulation of these progenitors. Unexpectedly, we encountered synaptic-like contacts between an extensive network of intraventricular axons containing serotonin (5HT) and B1 cells.
In Aim 3, we will investigate the organization of these supraependymal axons, characterize the specific sets of 5HT receptors expressed by B1 cells, and determine the contribution of 5HT to postnatal V-SVZ neurogenesis. Self-renewal and multipotency are fundamental questions in the field. How new neurons and oligodendrocytes continue to be produced during postnatal life is essential to our understanding of postnatal brain development and suggests new approaches for brain repair. 2011)

Public Health Relevance

Adult neural stem cells (NSCs) in the walls of the brain lateral ventricles have been extensively studied, as they are a possible source of new neurons and myelinating glial cells for brain repair, but also the origin of some brain tumors. Fundamental understanding of their mode of division, the origin of glia, and factors within the postnatal brain that regulate NSC proliferation remain unknown. The proposed work addresses these questions in three Aims based on: new methods to study the behavior of adult NSCs live;new preliminary data of a subregion of the V-SVZ where many oligodendrocytes are born;and a major axonal plexus inside the ventricle that contacts adult NSCs.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01NS028478-22
Application #
8760127
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Lavaute, Timothy M
Project Start
Project End
Budget Start
Budget End
Support Year
22
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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