title: HB-GAM inhibits proliferation and enhances differentiation of neural stem cells.
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.
authors.affiliation: Neuroscience Center, Department of Biosciences and Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland. anni.hienola@helsinki.fi
authors.forename: Anni
authors.initials: A
authors.lastname: Hienola
authors.forename: Mari
authors.initials: M
authors.lastname: Pekkanen
authors.forename: Erkki
authors.initials: E
authors.lastname: Raulo
authors.forename: Päivi
authors.initials: P
authors.lastname: Vanttola
authors.forename: Heikki
authors.initials: H
authors.lastname: Rauvala
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D016207:Cytokines / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology; D006133:Growth Substances / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D006133:Growth Substances; D019812:Heparan Sulfate Proteoglycans; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; C066845:pleiotrophin; D004815:Epidermal Growth Factor; C496349:Fgfr1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1