Abstract
Despite recent studies showing that inhibition of autophagy depletes the hematopoietic stem cell pool and increases intracellular reactive oxygen species (ROS), it remains unknown whether autophagy is essential in the maintenance of other stem cells. Moreover, it is unclear whether and how the aberrant ROS increase causes depletion of stem cells. Here we report that ablation of FIP200 (also known as Rb1cc1), a gene essential for autophagy induction in mammalian cells, results in a progressive loss of neural stem cells (NSCs) and impairment in neuronal differentiation specifically in the postnatal brain, but not the embryonic brain, in mice. The defect in maintaining the postnatal NSC pool was caused by p53-dependent apoptotic responses and cell cycle arrest. However, the impaired neuronal differentiation was rescued by treatment with the antioxidant N-acetylcysteine but not by p53 inactivation. These data reveal that FIP200-mediated autophagy contributes to the maintenance and functions of NSCs through regulation of oxidative state.
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Acknowledgements
We are grateful to J. Yuan of Harvard Medical School for Spautin-1. We thank our laboratory colleagues for their discussions, help throughout the project and comments of the manuscript. This research was supported by US National Institutes of Health grant GM052890 to J.-L.G.
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C.W. conducted the study, analyzed the data and wrote the manuscript; C.-C.L. generated some mouse lines; Z.C.B. genotyped the mice; Y.Z. analyzed the data; J.-L.G. conceived and supervised the study, analyzed the data and co-wrote the manuscript.
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Wang, C., Liang, CC., Bian, Z. et al. FIP200 is required for maintenance and differentiation of postnatal neural stem cells. Nat Neurosci 16, 532–542 (2013). https://doi.org/10.1038/nn.3365
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DOI: https://doi.org/10.1038/nn.3365
