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Research Article | Spotlight

FBXL5 Inactivation in Mouse Brain Induces Aberrant Proliferation of Neural Stem Progenitor Cells

Takayoshi Yamauchi, Masaaki Nishiyama, Toshiro Moroishi, Atsuki Kawamura, Keiichi I. Nakayama
Takayoshi Yamauchi
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
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Masaaki Nishiyama
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
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Toshiro Moroishi
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
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Atsuki Kawamura
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
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Keiichi I. Nakayama
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
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DOI: 10.1128/MCB.00470-16
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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 die in utero at 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.

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FBXL5 Inactivation in Mouse Brain Induces Aberrant Proliferation of Neural Stem Progenitor Cells
Takayoshi Yamauchi, Masaaki Nishiyama, Toshiro Moroishi, Atsuki Kawamura, Keiichi I. Nakayama
Molecular and Cellular Biology Mar 2017, 37 (8) e00470-16; DOI: 10.1128/MCB.00470-16

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FBXL5 Inactivation in Mouse Brain Induces Aberrant Proliferation of Neural Stem Progenitor Cells
Takayoshi Yamauchi, Masaaki Nishiyama, Toshiro Moroishi, Atsuki Kawamura, Keiichi I. Nakayama
Molecular and Cellular Biology Mar 2017, 37 (8) e00470-16; DOI: 10.1128/MCB.00470-16
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KEYWORDS

brain
F-Box Proteins
neural stem cells
SCF complex
brain development
iron regulation
ligase
mTOR
neural stem cell
oxidative stress
ubiquitination

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