![Sample our Bioscience journals, sign in here to start your access, Latest two full volumes FREE to you for 14 days]({"type":"image" , "src" : "/sda/5925/TOC-Subject-Sample-2021-Bioscience.jpg"})
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.
ACKNOWLEDGMENTS
We thank E. Koba, K. Motomura, and N. Kinoshita for technical assistance.
We declare that we have no conflicts of interest.
This study was performed as a research program of the Project for Development of Innovative Research on Cancer Therapeutics (P-Direct) of the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan. It was also funded in part by KAKENHI grants (25221303 and 26640080) from MEXT. T.Y. was supported by a Research Fellowship of the Japan Society for the Promotion of Science for Young Scientists.