title: FIP200 is required for maintenance and differentiation of postnatal neural stem cells.
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.
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Chenran
authors.initials: C
authors.lastname: Wang
authors.forename: Chun-Chi
authors.initials: CC
authors.lastname: Liang
authors.forename: Z Christine
authors.initials: ZC
authors.lastname: Bian
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Jun-Lin
authors.initials: JL
authors.lastname: Guan
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D000071183:Autophagy-Related Proteins; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002552:Cerebral Ventricles / Q000166:cytology; D002738:Chloroquine / Q000494:pharmacology; D018891:Dentate Gyrus / Q000166:cytology; D003997:Dicarbethoxydihydrocollidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000188:drug therapy / Q000235:genetics; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D017382:Reactive Oxygen Species / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D012794:Sialic Acids / Q000378:metabolism; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000071183:Autophagy-Related Proteins; D005904:Glial Fibrillary Acidic Protein; C490981:Gtf2h1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D039842:Neural Cell Adhesion Molecule L1; C428743:Rb1cc1 protein, mouse; D017382:Reactive Oxygen Species; D055748:SOXB1 Transcription Factors; D012794:Sialic Acids; C527783:Sox2 protein, mouse; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C514241:dihydroethidine; C103469:polysialyl neural cell adhesion molecule; D051758:Transcription Factor TFIIH; D003997:Dicarbethoxydihydrocollidine; D002738:Chloroquine; D001973:Bromodeoxyuridine; D000111:Acetylcysteine
references.citation: Nat Neurosci. 2008 Oct;11(10):1153-61
references.pmid: 18758458
references.citation: Cell. 2007 Jan 26;128(2):325-39
references.pmid: 17254970
references.citation: Science. 1992 Mar 27;255(5052):1707-10
references.pmid: 1553558
references.citation: Cell. 2011 Nov 11;147(4):728-41
references.pmid: 22078875
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):19860-5
references.pmid: 19910529
references.citation: Cell. 2011 Sep 30;147(1):223-34
references.pmid: 21962518
references.citation: Cell Metab. 2007 Dec;6(6):458-71
references.pmid: 18054315
references.citation: Neuron. 1996 Oct;17(4):595-606
references.pmid: 8893018
references.citation: Cell. 2008 Feb 22;132(4):645-60
references.pmid: 18295581
references.citation: Cell. 1999 Jun 11;97(6):703-16
references.pmid: 10380923
references.citation: Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17528-32
references.pmid: 15574494
references.citation: Development. 2006 Jan;133(2):363-9
references.pmid: 16368933
references.citation: Nat Cell Biol. 2010 Oct;12(10):999-1006
references.pmid: 20835244
references.citation: Nat Cell Biol. 2008 Apr;10(4):385-94
references.pmid: 18344989
references.citation: Annu Rev Genet. 2009;43:67-93
references.pmid: 19653858
references.citation: Nat Cell Biol. 2010 Oct;12(10):1007-13
references.pmid: 20852629
references.citation: Cell Stem Cell. 2009 Nov 6;5(5):527-39
references.pmid: 19896443
references.citation: J Biol Chem. 2009 Feb 27;284(9):6004-13
references.pmid: 19106106
references.citation: J Exp Med. 2011 Mar 14;208(3):455-67
references.pmid: 21339326
references.citation: Stem Cells. 2006 Sep;24(9):2110-9
references.pmid: 16728559
references.citation: Nat Neurosci. 2002 Apr;5(4):308-15
references.pmid: 11896398
references.citation: J Biol Chem. 2010 Jan 29;285(5):3499-509
references.pmid: 19940130
references.citation: Nat Cell Biol. 2010 Oct;12(10):993-8
references.pmid: 20818388
references.citation: Genes Dev. 2005 Mar 15;19(6):756-67
references.pmid: 15769947
references.citation: Blood. 2010 Dec 2;116(23):4806-14
references.pmid: 20716775
references.citation: Antioxid Redox Signal. 2005 Nov-Dec;7(11-12):1456-67
references.pmid: 16356108
references.citation: Cold Spring Harb Perspect Biol. 2010 Dec;2(12):a000893
references.pmid: 20463001
references.citation: Cell Stem Cell. 2011 Jan 7;8(1):59-71
references.pmid: 21211782
references.citation: Nature. 2006 Jun 15;441(7095):880-4
references.pmid: 16625205
references.citation: Cell. 2009 May 1;137(3):413-31
references.pmid: 19410540
references.citation: Cell Stem Cell. 2009 Nov 6;5(5):540-53
references.pmid: 19896444
references.citation: J Cell Biol. 2000 Apr 17;149(2):423-30
references.pmid: 10769033
references.citation: J Cell Biol. 2006 Oct 9;175(1):121-33
references.pmid: 17015619
references.citation: J Clin Invest. 2009 Nov;119(11):3329-39
references.pmid: 19855132
references.citation: Nat Cell Biol. 2010 Jul;12(7):665-75
references.pmid: 20543840
references.citation: Nature. 2006 Jun 15;441(7095):885-9
references.pmid: 16625204
references.citation: Nat Rev Drug Discov. 2008 Dec;7(12):979-87
references.pmid: 19043449
references.citation: Neuron. 2011 May 26;70(4):687-702
references.pmid: 21609825
references.citation: Genes Dev. 2011 Jul 15;25(14):1510-27
references.pmid: 21764854
references.citation: Nat Med. 2006 Apr;12(4):446-51
references.pmid: 16565722
references.citation: Annu Rev Neurosci. 2009;32:149-84
references.pmid: 19555289
references.citation: Int J Biochem Cell Biol. 2004 Dec;36(12):2491-502
references.pmid: 15325587
references.citation: Nat Rev Neurosci. 2006 Feb;7(2):93-102
references.pmid: 16429119
references.citation: J Cell Biol. 2008 May 5;181(3):497-510
references.pmid: 18443221
references.citation: Science. 2000 Feb 25;287(5457):1433-8
references.pmid: 10688783
references.citation: J Neurosci. 2006 Jan 25;26(4):1107-16
references.pmid: 16436596
references.citation: Mol Cell. 2011 Nov 4;44(3):491-501
references.pmid: 22055193
references.citation: Cancer Cell. 2005 Aug;8(2):119-30
references.pmid: 16098465
references.citation: Ann Neurol. 2001 May;49(5):627-35
references.pmid: 11357953
references.citation: Nat Neurosci. 2005 Jul;8(7):865-72
references.pmid: 15951811
references.citation: Mol Cell Biol. 2007 Jul;27(13):4931-7
references.pmid: 17452461
references.citation: Cancer Cell. 2009 Jun 2;15(6):514-26
references.pmid: 19477430