HB-GAM inhibits proliferation and enhances differentiation of neural stem cells

• Published in: Molecular and cellular neuroscience 2004-05, Vol.26 (1), p.75-88
• Main Authors: Hienola, Anni, Pekkanen, Mari, Raulo, Erkki, Vanttola, Päivi, Rauvala, Heikki
• Format: Article
• Language: English
• Subjects: Animals; Carrier Proteins - genetics; Carrier Proteins - physiology; Cell Differentiation - genetics; Cell Differentiation - physiology; Cell Division - genetics; Cells, Cultured; Cerebral Cortex - cytology; Cerebral Cortex - embryology; Cerebral Cortex - metabolism; Cytokines - deficiency; Cytokines - genetics; Cytokines - physiology; Epidermal Growth Factor - metabolism; Epidermal Growth Factor - pharmacology; Female; Fibroblast Growth Factor 2 - metabolism; Fibroblast Growth Factor 2 - pharmacology; Growth Substances - deficiency; Growth Substances - genetics; Growth Substances - physiology; Heparan Sulfate Proteoglycans - metabolism; Intermediate Filament Proteins - metabolism; Male; Mice; Mice, Knockout; Nerve Tissue Proteins - metabolism; Nestin; Neurons - cytology; Neurons - metabolism; Phosphorylation - drug effects; Receptor Protein-Tyrosine Kinases - metabolism; Receptor, Fibroblast Growth Factor, Type 1; Receptors, Fibroblast Growth Factor - metabolism; Stem Cells - cytology; Stem Cells - metabolism
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2004.01.018

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.