Neural stem and progenitor cells (NSPC) offer enormous potential for treating degenerative diseases or traumas of the nervous system. In adult mammalian species, NSC primarily reside in the lateral ventricle walls, where they proliferate and differentiate to produce new neurons and glial cells. It is now evident that microenvironmental cues regulate NSPC proliferation in the """"""""niche"""""""" where the cells reside. However, the intrinsic systems that govern the neurogenic niche are poorly understood. Our overall goal is to understand how NSPC, endogenous or transplanted, function within an individual, to eventually replace lost cells. This fundamental understanding is crucial for designing new therapies for neural cells dying due to trauma, degeneration and demyelination. Based on our published data, we hypothesize that the new extracellular structures """"""""fractones"""""""" we characterized in direct contact with NSPC in the neurogenic niche of the adult mammalian brain, mediate and regulate the production of new neurons and glial cells throughout adulthood. Our preliminary results indicate that the mechanisms implicated pertain to growth factor/extracellular matrix interactions at the NSPC/fractone interface. The objective of this proposal is to determine whether and how fractones intervene in the process of NSPC proliferation induced by the neurogenic growth factor FGF-2. We found that fractones bind and concentrate FGF-2 in vivo, by a mechanism that is heparan sulfate proteoglycan (HSPG) dependent.
Our specific aims are to determine: 1) whether FGF-2 binding to fractones is responsible for FGF-2 induced neurogenesis in the niche; 2) whether NSPC proliferate in contact with fractones that have bound FGF-2; 3) the role of the fractone component perlecan (a major HSPG) on FGF-2-induced NSPC proliferation in the niche.
For specific aim 1, we will use biotinylated FGF-2 as a tracer and inducer of NSPC proliferation, and heparatinase, both injected in vivo in the brain of adult mice to determine whether cutting the binding of biotinylated FGF-2 from fractone-borne HSPG annihilates neurogenesis induced by FGF-2. Immunofluorescence will be used to visualize post-mitotic cells that have incorporated bromodeoxyuridine and biotinylated FGF-2.
For specific aim 2, we will use biotinylated FGF-2 to identify the spatial relationships between fractones that have bound biotinylated FGF-2 and the emerging cells that have proliferated in response to biotinylated FGF-2.
For specific aim 3, we will use transgenic animals (perlecan-null mice) to determine how the lack of perlecan is detrimental to NSPC proliferation induced by biotinylated FGF-2 in the niche. These experiments will allow us to determine whether fractones promote NSPC proliferation induced by FGF-2 in the neural stem cell niche. If demonstrated, fractones will be considered as crucial components that regulate the neural stem cell niche throughout adulthood. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS057675-01A1
Application #
7387583
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Owens, David F
Project Start
2007-09-30
Project End
2009-07-31
Budget Start
2007-09-30
Budget End
2008-07-31
Support Year
1
Fiscal Year
2007
Total Cost
$201,469
Indirect Cost
Name
University of Hawaii
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
965088057
City
Honolulu
State
HI
Country
United States
Zip Code
96822
Douet, V; Kerever, A; Arikawa-Hirasawa, E et al. (2013) Fractone-heparan sulphates mediate FGF-2 stimulation of cell proliferation in the adult subventricular zone. Cell Prolif 46:137-45
Douet, Vanessa; Arikawa-Hirasawa, Eri; Mercier, Frederic (2012) Fractone-heparan sulfates mediate BMP-7 inhibition of cell proliferation in the adult subventricular zone. Neurosci Lett 528:120-5
Mercier, Frederic; Arikawa-Hirasawa, Eri (2012) Heparan sulfate niche for cell proliferation in the adult brain. Neurosci Lett 510:67-72
Mercier, Frederic; Kwon, Youngsu Cho; Douet, Vanessa (2012) Hippocampus/amygdala alterations, loss of heparan sulfates, fractones and ventricle wall reduction in adult BTBR T+ tf/J mice, animal model for autism. Neurosci Lett 506:208-13
Mercier, Frederic; Cho Kwon, Youngsu; Kodama, Rich (2011) Meningeal/vascular alterations and loss of extracellular matrix in the neurogenic zone of adult BTBR T+ tf/J mice, animal model for autism. Neurosci Lett 498:173-8