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.
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ABSTRACT: Throughout life, neural stem cells proliferate and differentiate in restricted zones of the brain, termed niches, to produce new neurons and glial cells. In these niches, growth factors and extracellular matrix (ECM) molecules determine the fate of neural stem and progenitor cells (NSPC). However, the precise compounds and the mechanisms that regulate growth factors and other signaling molecules in the niches are unknown. Based on the evidence that NSPCs proliferate next to blood vessels in the dentate gyrus, the concept of a vascular niche for neurogenesis has been initially proposed. In the subventricular zone of the lateral ventricle, the most neurogenic zone in adulthood, we have found that NSPC directly contact a novel type of ECM structure that we have named fractones. Fractones contain heparan sulfate proteoglycans (HSPG) that collect and concentrate the neurogenic growth factor FGF2 at the NSPC surface and likely direct its signaling via tyrosine kinase receptors. Our preliminary results indicate that FGF2 binding to fractone-HSPG is essential for activating FGF2 at the NSPC surface. Moreover, we have found fractones express diverse HSPG at the surface of proliferating NSPC during development, even before the brain vasculature emerges. Therefore, fractones hold considerable promise for promoting growth factors at the stem cell surface to ultimately regulate neurogenesis during development and adulthood. 4.1 Introduction to the Concept of the Neural Stem Cell Niche Neural stem cells proliferate and differentiate to produce new neurons and glial cells in restricted zones of the adult brain: the subventricular zone (SVZ) of the lateral ventricle, the rostral migratory streams (RMS), the subcallosum zone (SCZ), the olfactory bulb (OB), and the polymorph and granular layers of the dentate gyrusNeurogenesis in the adult brain, Edited by A Alvarez-Buylla, JM Parent, M Sawamoto, T Seki, 01/2011: pages 109-136; Springer-Verlag.
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ABSTRACT: Pleiotrophin (PTN) is an extracellular matrix-associated protein with neurotrophic and neuroprotective effects that is involved in a variety of neurodevelopmental processes. Data regarding the cognitive-behavioral and neuroanatomical phenotype of pleiotrophin knockout (KO) mice is limited. The purpose of this study was to more fully characterize this phenotype, with emphasis on the domains of learning and memory, cognitive-behavioral flexibility, exploratory behavior and anxiety, social behavior, and the neuronal and vascular microstructure of the lateral entorhinal cortex (EC). PTN KOs exhibited cognitive rigidity, heightened anxiety, behavioral reticence in novel contexts and novel social interactions suggestive of neophobia, and lamina-specific decreases in neuronal area and increases in neuronal density in the lateral EC. Initial learning of spatial and other associative tasks, as well as vascular density in the lateral EC, was normal in the KOs. These data suggest that the absence of PTN in vivo is associated with disruption of specific cognitive and affective processes, raising the possibility that further study of PTN KOs might have implications for the study of human disorders with similar features.PLoS ONE 07/2014; 9(7):e100597. DOI:10.1371/journal.pone.0100597 · 3.53 Impact Factor