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Published on: March 4, 2015
FBXL5 Inactivation in Mouse Brain Induces Aberrant Proliferation of Neural Stem Progenitor Cells
Takayoshi Yamauchi1, Masaaki Nishiyama2, Toshiro Moroishi1
1Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
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.
Insights
FBXL5 deficiency in brain stem cells causes iron overload and uncontrolled cell growth. This study reveals FBXL5
Area of Science:
- Neuroscience
- Cell Biology
- Developmental Biology
Background:
- FBXL5 regulates iron metabolism in mammalian cells.
- Systemic FBXL5 deficiency in mice causes embryonic lethality due to iron overload.
- The role of FBXL5 in brain development remains unclear due to early embryonic lethality.
Purpose of the Study:
- To investigate the role of FBXL5 in mammalian brain development.
- To examine the effects of FBXL5 deficiency in neural stem progenitor cells (NSPCs).
Main Methods:
- Generated mice with FBXL5 deficiency specifically in NSPCs.
- Analyzed NSPC proliferation and astroglia numbers in the cerebral cortex.
- Assessed iron levels, reactive oxygen species generation, and mTOR signaling.
Main Results:
- FBXL5-deficient mice exhibited increased NSPC and astroglia proliferation.
- FBXL5 deficiency led to iron accumulation and increased reactive oxygen species.
- Aberrant mTOR signaling activation was observed in mutant brains.
Conclusions:
- FBXL5 is crucial for regulating NSPC proliferation during brain development.
- FBXL5 deficiency disrupts iron homeostasis, leading to oxidative stress and altered brain development.
- Targeting FBXL5 may offer therapeutic strategies for neurodevelopmental disorders.
