title: Progranulin enhances neural progenitor cell proliferation through glycogen synthase kinase 3β phosphorylation.
abstract: Progranulin (PGRN) is an estrogen-inducible growth factor thought to affect multiple processes in the CNS, including brain sexual differentiation, adult neurogenesis in the hippocampus, and development of neurodegenerative diseases. However, the precise physiological functions of PGRN in individual nerve cells are not fully understood. The aim of the present study was to enhance the understanding of PGRN function in the CNS by investigating the effects of PGRN on neural progenitor cells (NPCs). We found that significant amounts of endogenous PGRN were secreted from isolated NPCs in cultures. To assess the bioactivities of endogenous and exogenous PGRN, we studied NPCs derived from wild-type mice (WT-NPCs) and PGRN-deficient mice (KO-NPCs). We found that proliferation of KO-NPCs was significantly enhanced by PGRN treatment; however, PGRN treatment apparently did not affect proliferation of WT-NPCs perhaps because of the high levels of endogenous PGRN expression. NPC death and asymmetric cellular division of KO-NPCs and WT-NPCs, which results in production of neural stem cells, astrocytes, or oligodendrocytes, were not affected by PGRN treatment. We also investigated the signaling mechanism(s) that mediate PGRN-induced NPC proliferation and found that phosphorylation of serine 9 (S9) of glycogen synthase kinase 3-beta (GSK3β), which was dependent on phosphatidylinositol 3-kinase (PI3K) activity, was induced by PGRN treatment. In addition, a GSK3β-specific inhibitor enhanced NPC proliferation. Taken together, our observations indicate that PGRN enhanced NPC proliferation, at least in part, via inducing GSK3β phosphorylation.
authors.affiliation: Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nedachi
authors.forename: T
authors.initials: T
authors.lastname: Kawai
authors.forename: T
authors.initials: T
authors.lastname: Matsuwaki
authors.forename: K
authors.initials: K
authors.lastname: Yamanouchi
authors.forename: M
authors.initials: M
authors.lastname: Nishihara
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation; D005617:Chlorofluorocarbons, Methane / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D000077155:Granulins; D006493:Heparin / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000502:physiology*; D007381:Intermediate Filament Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D000077153:Progranulins; D012694:Serine / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000925:Anticoagulants; D005617:Chlorofluorocarbons, Methane; D002867:Chromones; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D007381:Intermediate Filament Proteins; D009025:Morpholines; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D000077153:Progranulins; D014404:Tubulin; C462941:beta3 tubulin, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D012694:Serine; D006493:Heparin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D001973:Bromodeoxyuridine; C007782:dichlorodifluoromethane; D000077191:Wortmannin