Abstract
Proliferation of neural stem cells in the embryonic cerebral cortex is regulated by many growth factors and their receptors. Among the key molecules stimulating stem cell proliferation are FGF-2 and the FGF receptor-1. This ligand-receptor system is highly dependent on the surrounding heparan sulfates. We have found that heparin-binding growth-associated molecule (HB-GAM, also designated as pleiotrophin) regulates neural stem cell proliferation in vivo and in vitro. Deficiency of HB-GAM results in a pronounced, up to 50% increase in neuronal density in the adult mouse cerebral cortex. This phenotype arises during cortical neurogenesis, when HB-GAM knockout embryos display an enhanced proliferation rate as compared to wild-type embryos. Further, our in vitro studies show that exogenously added HB-GAM inhibits formation and growth of FGF-2, but not EGF, stimulated neurospheres, restricts the number of nestin-positive neural stem cells, and inhibits FGF receptor phosphorylation. We propose that HB-GAM functions as an endogenous inhibitor of FGF-2 in stem cell proliferation in the developing cortex.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / physiology*
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Cell Differentiation / genetics
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Cell Differentiation / physiology*
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Cell Division / genetics
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Cells, Cultured
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Cerebral Cortex / cytology
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Cerebral Cortex / embryology*
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Cerebral Cortex / metabolism
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Cytokines / deficiency
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Cytokines / genetics
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Cytokines / physiology*
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Epidermal Growth Factor / metabolism
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Epidermal Growth Factor / pharmacology
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Female
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Fibroblast Growth Factor 2 / metabolism
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Fibroblast Growth Factor 2 / pharmacology
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Growth Substances / deficiency
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Growth Substances / genetics
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Growth Substances / physiology*
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Heparan Sulfate Proteoglycans / metabolism
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Intermediate Filament Proteins / metabolism
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Male
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Mice
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Mice, Knockout
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Nerve Tissue Proteins / metabolism
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Nestin
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Neurons / cytology
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Neurons / metabolism*
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Phosphorylation / drug effects
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptor, Fibroblast Growth Factor, Type 1
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Receptors, Fibroblast Growth Factor / metabolism
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Stem Cells / cytology
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Stem Cells / metabolism*
Substances
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Carrier Proteins
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Cytokines
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Growth Substances
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Heparan Sulfate Proteoglycans
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Intermediate Filament Proteins
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Nerve Tissue Proteins
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Nes protein, mouse
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Nestin
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Receptors, Fibroblast Growth Factor
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Fibroblast Growth Factor 2
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pleiotrophin
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Epidermal Growth Factor
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Fgfr1 protein, mouse
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Receptor Protein-Tyrosine Kinases
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Receptor, Fibroblast Growth Factor, Type 1