Neural stem cells (NSCs) in the adult mammalian brain have been demonstrated to play important roles in the plasticity of higher brain function and repair and regeneration after brain damage. Yet, our understanding of the regulation of adult NSCs at the molecular level remains sketchy, and this is one of the reasons for why strategies to harness the capacity of endogenous NSCs for brain repair have not yet made sufficient progress for clinical applications. The goal of this study is to fill in this current knowledge gap by identifying crucial regulatory mechanisms in adult NSCs using mouse as a model system. In particular, our recent studies have shown that the homeodomain transcription factor (TF) Gsx2 and basic helix-loop-helix TF Ascl1, which have been well known for their essential roles in embryonic brain development, play vital roles in controlling NSCs in the adult subventricular zone (SVZ). Importantly, we found that Gsx2 and Ascl1 control adult-specific regulatory steps in NSCs. We also have shown that these TFs play essential roles in injury-induced neurogenesis. Our preliminary studies further suggest that unlike in embryos in which Gsx2 and Ascl1 act in a linear cascade (Gsx2 Ascl1 neurogenesis), their cross-inhibition plays a key role in controlling the fate of adult NSCs. Based on these novel findings and in vivo tools, we will test the hypothesis that Gsx2 and Ascl1, as well as their downstream effectors, play crucial roles in controlling NSCs in adult-specific manners under intact and injury conditions in the following three specific aims:
Aim 1 will reveal novel mechanisms for lineage progression of adult NSCs through studies on Gsx2, Ascl1, and their downstream targets. ;
Aim 2 will reveal novel mechanisms for regional specification of NSCs and neuronal subtype specification of olfactory bulb (OB) interneurons through studies on the regulation of Gsx2 and its downstream factors.;
Aim 3 will reveal novel mechanisms for injury-induced neurogenesis through studies on the regulation of the expression and action of Gsx2.

Public Health Relevance

Neural stem cells (NSCs) continuously produce new neurons and glia cells in the adult brain. The new neural circuits they form play important roles in both the plasticity of higher brain function and repair and regeneration after injury. This study aims t better understand the molecular mechanisms underlying the regulation of adult NSCs in the intact and injured brain using mice as a model. Thus, the outcomes of this study will have significant contributions to the promotion of human health and welfare.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS069893-06
Application #
8883856
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Lavaute, Timothy M
Project Start
2010-04-01
Project End
2020-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
6
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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