title: FBXL5 Inactivation in Mouse Brain Induces Aberrant Proliferation of Neural Stem Progenitor Cells.
abstract: FBXL5 is the substrate recognition subunit of an SCF-type ubiquitin ligase that serves as a master regulator of iron metabolism in mammalian cells. We previously showed that mice with systemic deficiency of FBXL5 fail to sense intracellular iron levels and diein uteroat embryonic day 8.5 (E8.5) as a result of iron overload and subsequent oxidative stress. This early embryonic mortality has thus impeded study of the role of FBXL5 in brain development. We have now generated mice lacking FBXL5 specifically in nestin-expressing neural stem progenitor cells (NSPCs) in the brain. Unexpectedly, the mutant embryos manifested a progressive increase in the number of NSPCs and astroglia in the cerebral cortex. Stabilization of iron regulatory protein 2 (IRP2) as a result of FBXL5 deficiency led to accumulation of ferrous and ferric iron as well as to generation of reactive oxygen species. Pharmacological manipulation suggested that the phenotypes of FBXL5 deficiency are attributable to aberrant activation of mammalian target of rapamycin (mTOR) signaling. Our results thus show that FBXL5 contributes to regulation of NSPC proliferation during mammalian brain development.
authors.affiliation: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Yamauchi
authors.affiliation: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan nishiyam@bioreg.kyushu-u.ac.jp nakayak1@bioreg.kyushu-u.ac.jp.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Nishiyama
authors.affiliation: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Moroishi
authors.affiliation: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Atsuki
authors.initials: A
authors.lastname: Kawamura
authors.affiliation: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan nishiyam@bioreg.kyushu-u.ac.jp nakayak1@bioreg.kyushu-u.ac.jp.
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism*; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000166:cytology; D044783:F-Box Proteins / Q000378:metabolism*; D017353:Gene Deletion; D007501:Iron / Q000378:metabolism; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D018384:Oxidative Stress; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D044783:F-Box Proteins; C569388:FBXL5 protein, mouse; D007501:Iron; D058570:TOR Serine-Threonine Kinases
keywords: SCF complex; brain development; iron regulation; ligase; mTOR; neural stem cell; oxidative stress; ubiquitination