A major goal of developmental neurobiology is to define mechanisms that regulate the developmental potential of neural progenitor populations under normal physiological and pathological conditions. The subventricular zone (SVZ) contains a mosaic of neural progenitor cells (NPCs), which maintain their mitotic and differentiation potential throughout their life span. NPCs provide the brain with the potential to replenish damaged glia and neurons through spontaneous gliogenesis and neurogenesis. Glutamic acid decarboxylase 65 (GAD65) and Doublecortin (Dcx)-expressing cells constitute a major progenitor population of the adult SVZ ( ). Under normal conditions, these cells migrate along the rostral migratory stream toward the olfactory bulb to generate inhibitory interneurons. Recent studies demonstrating the ability of NPCs to change their lineage potential after genetic manipulation have led us to hypothesize that pathological stimuli may also induce lineage plasticity in native NPCs. Our preliminary analysis in GAD-GFP and Dcx-GFP transgenic mice indicate that: i) after lysolecithin (LPC)-induced focal demyelination of the corpus callosum (CC), or after perinatal hypoxia (HX), GAD65-GFP+ and Dcx-GFP+ progenitor cells migrate from the SVZ into the CC;ii) GAD-GFP+ and Dcx-GFP+ cells display lineage potential plasticity in CC, as they generate OLs after demyelination or after HX, and iii) chordin is upregulated in the SVZ after demyelination and promotes oligodendrogenesis from GAD-GFP+ and Dcx-GFP+ progenitors in culture and in vivo. Based on these findings, we plan to investigate whether lineage plasticity of both adult and perinatal SVZ neuronal progenitor cells occurs under pathological conditions involving the white matter, and to identify endogenous signals that promote oligodendrogenesis from GAD- and Dcx- expressing progenitors of the SVZ. In order to compare early postnatal and adult neuronal progenitor responses and signals, we will use two distinct animal models of white matter injury, i.e. toxin-induced focal demyelination in adults and perinatal HX. First, we will establish whether SVZ neuronal progenitors generate oligodendrocytes after focal demyelination in the adult brain. Second, we will determine whether SVZ neuronal progenitors generate oligodendrocytes after HX in the early postnatal brain. Finally, we will identify endogenous cellular signals that promote oligodendrogenesis from SVZ progenitors in the early postnatal and adult brain. Together, these studies will not only shed light on crucial cellular and molecular mechanisms of oligodendrogenesis from different NPC populations, but might also lead to the development of new therapeutic approaches aimed at lessening the long-term neurological sequelae of white matter injury.

Public Health Relevance

A Common Glial-Neuronal Progenitor in Postnatal Brain PI: Vittorio Gallo, PhD A major goal of developmental neurobiology is to define mechanisms that regulate the developmental potential of neural progenitor populations under normal physiological and pathological conditions. The subventricular zone (SVZ) contains a mosaic of neural progenitor cells (NPCs), which maintain their mitotic and differentiation potential throughout their life span. NPCs provide the brain with the potential to replenish damaged glia and neurons through spontaneous gliogenesis and neurogenesis. We propose to investigate whether lineage plasticity of both adult and perinatal SVZ neuronal progenitor cells occurs under pathological conditions involving the white matter, and to identify endogenous signals that promote oligodendrogenesis from NPCs of the SVZ.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045702-10
Application #
8659515
Study Section
Special Emphasis Panel (ZRG1-MDCN-N (02))
Program Officer
Owens, David F
Project Start
2004-09-15
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
10
Fiscal Year
2014
Total Cost
$365,037
Indirect Cost
$152,806
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
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