The size of the neural stem cells (NSCs) population of the subventricular zone (SVZ) at any time is the result of several ongoing processes, including self-renewal, cell differentiation, and Cell death. Maintaining the balance between NSC and neural progenitor cells (NPCs) in the SVZ is critical to supply the brain with specific neural populations, both under normal conditions or after injury. As NSCs are also a source of regenerating neurons and glia after a variety of pathological insults, elucidation of the cellular and molecular signals that regulate the size of NSC and NPC pool in the SVZ will provide crucial information for cell repair strategies that are directed to mobilization of endogenous NSCs. We have recently analyzed the CNPhEGFR mouse, in which EGFR signaling is enhanced and CA/P-expressing (NG2*Olig2*Mash*) progenitor cells are expanded in the SVZ. A preliminary analysis of the postnatal and adult SVZ-niche in the CNPhEGFR mouse demonstrates that C/VP-expressing cells regulate the proliferation and self-renewal of NSCs in the SVZ-niche. Microarray data also indicate that the Notch signaling pathway is downregulated in the SVZ of the CA/P-hEGFR mouse. Our recent data also show that expansion of the CA/P-expressing progenitor cells pool after acute demyelination of the corpus caliosum (CC) is associated with downregulation of Notch signaling, and with reduced NSC proliferation and self-renewal. We will use a variety of transgenic and mutant mouse strains, including the C/VP-hEGFR, A/62-dsRED, GFAP-GFP, Egfr*"^ and C/S/P-EGFP mouse, along with two models of demyelination of the cortical white matter (lysolecithin-induced focal demyelination;dietary cuprizohe) to test the hypothesis that NPCs in the SVZ play a crucial role in regulating NSC number through the EGFR and Notch signaling pathways. This research will uncover homeostatic mechanisms that might occur between different types of SVZ cells under normal conditions, and will provide crucial information on possible alterations of specific signaling pathways that arise under pathological conditions or after^brain injury. Our findings will be particularly relevant to cellbased repair therapies that involve the use of endogenous NSCs and NPCs of the postnatal and adult SVZ.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Transition Award (R00)
Project #
5R00NS057944-05
Application #
8204524
Study Section
Special Emphasis Panel (NSS)
Program Officer
Utz, Ursula
Project Start
2007-06-01
Project End
2012-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$228,812
Indirect Cost
$79,587
Name
State University New York Stony Brook
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
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Palazuelos, Javier; Klingener, Michael; Aguirre, Adan (2014) TGF? signaling regulates the timing of CNS myelination by modulating oligodendrocyte progenitor cell cycle exit through SMAD3/4/FoxO1/Sp1. J Neurosci 34:7917-30
Klingener, Michael; Chavali, Manideep; Singh, Jagdeep et al. (2014) N-cadherin promotes recruitment and migration of neural progenitor cells from the SVZ neural stem cell niche into demyelinated lesions. J Neurosci 34:9590-606
Aguirre, Adan; Rubio, Maria E; Gallo, Vittorio (2010) Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal. Nature 467:323-7