Neural stem cells (NSCs) are retained in the walls of the lateral ventricle in the largest postnatal germinal niche: the ventricular-subventricular zone (V-SVZ). Past work - supported by this proposal - identified a population of astroglia (Bl cells) as the NSCs in the adult mouse brain. During the past few years, the epithelial organization of the V- SVZ was demonstrated;in particular, the apical, intermediate, and basal domains of NSCs were identified. 81 cells'apical compartment shares the ventricular surface with ependymal cells, which unlike Bl cells do not divide, but are essential for cerebrospinal fluid (CSF) circulation and homeostasis. The CSF, in turn, contains factors that regulate adult neurogenesis and neuronal migration within this niche. By adult stages ependymal cells form conspicuous rosettes that surrounds Bl cells' apical compartment in structures referred to as pinwheels. The lineage leading to the formation of these two important cell populations, and the cellular and molecular mechanisms that pattern the ependymal layer, remain unknown. Preliminary data suggests that NSCs and ependymal cells share common progenitors. More importantly, these data suggest that postnatal Bl cells are not a simple continuation of embryonic lineages of NSCs. Instead, the preliminary results suggest that postnatal B1 cells are produced during a restricted period of embryonic development and set apart from embryonic lineages to specifically function as postnatal NSCs. Curiously, the time of birth of ependymal cells coincides with the time of production of postnatal Bl cells. The goal of Aim 1 is to confirm the time during development when postnatal NSCs are produced and determine their lineage relationships to other embryonic progenitors.
In Aim 2, we will investigate the lineage relationship between ependymal cells and Bl cells.
Aim 3 will extend findings from the past few years indicating that primary cilia in embryonic progenitors are required for the patterning of the V-SVZ. Specifically, we present preliminary data that shows how mechano-sensory function of this organelle, through Polycystin 1 &2, is essential for the patterning of the ependymal layer. The work will provide fundamental insights on the lineage relationship between embryonic NSCs, postnatal Bl cells and ependynrial cells. In addition, we will investigate how physical forces acting upon the primary cilia on fetal progenitors cells, help pattern this important epithelium that controls the circulation of CSF. Aberrant pinwheel development could result in dysfunctionalpostnatal NSCs and aberrant CSF flow, both conditions that can have devastating effects in early brain development. The understanding of how this epithelium, with its combine germinal and circulatory functions, develops will provide new insights on early postnatal human brain development and brain repair.

Public Health Relevance

Two pooriy understood cell types, with apparently very dissimilar functions, share the epithelium that lines the adult' forebrain ventricles: ependymal cells and neural stem cells (NSCs). These two cell types, that during development become organized into polarized rosettes called pinwheels, combine two functions of great clinical interest: cerebrospinal fluid circulation and the postnatal generation of new neurons. In this proposal, the origin of adult neural stem cells in the fetal brain, their lineage relationship to ependymal cells and the mechanism by which they become organized into polarized pinwheels will be investigated. These findings could help understand the mechanism of hydrocephalus, a condition that afflicts 1 in 300 infants, and help develop new strategies for the use of postnatal neural stem cells for brain repair.

Agency
National Institute of Health (NIH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HD032116-20
Application #
8691937
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Nitkin, Ralph M
Project Start
Project End
Budget Start
Budget End
Support Year
20
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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