title: IGF-II promotes stemness of neural restricted precursors.
abstract: Insulin-like growth factor (IGF)-I and IGF-II regulate brain development and growth through the IGF type 1 receptor (IGF-1R). Less appreciated is that IGF-II, but not IGF-I, activates a splice variant of the insulin receptor (IR) known as IR-A. We hypothesized that IGF-II exerts distinct effects from IGF-I on neural stem/progenitor cells (NSPs) via its interaction with IR-A. Immunofluorescence revealed high IGF-II in the medial region of the subventricular zone (SVZ) comprising the neural stem cell niche, with IGF-II mRNA predominant in the adjacent choroid plexus. The IGF-1R and the IR isoforms were differentially expressed with IR-A predominant in the medial SVZ, whereas the IGF-1R was more abundant laterally. Similarly, IR-A was more highly expressed by NSPs, whereas the IGF-1R was more highly expressed by lineage restricted cells. In vitro, IGF-II was more potent in promoting NSP expansion than either IGF-I or standard growth medium. Limiting dilution and differentiation assays revealed that IGF-II was superior to IGF-I in promoting stemness. In vivo, NSPs propagated in IGF-II migrated to and took up residence in periventricular niches while IGF-I-treated NSPs predominantly colonized white matter. Knockdown of IR or IGF-1R using shRNAs supported the conclusion that the IGF-1R promotes progenitor proliferation, whereas the IR is important for self-renewal. Q-PCR revealed that IGF-II increased Oct4, Sox1, and FABP7 mRNA levels in NSPs. Our data support the conclusion that IGF-II promotes the self-renewal of neural stem/progenitors via the IR. By contrast, IGF-1R functions as a mitogenic receptor to increase precursor abundance.
authors.affiliation: Department of Neurology and Neuroscience, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA.
authors.forename: Amber N
authors.initials: AN
authors.lastname: Ziegler
authors.forename: Joel S
authors.initials: JS
authors.lastname: Schneider
authors.forename: Mei
authors.initials: M
authors.lastname: Qin
authors.forename: William A
authors.initials: WA
authors.lastname: Tyler
authors.forename: John E
authors.initials: JE
authors.lastname: Pintar
authors.forename: Diego
authors.initials: D
authors.lastname: Fraidenraich
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Wood
authors.forename: Steven W
authors.initials: SW
authors.lastname: Levison
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II