title: Spindle checkpoint deficiency is tolerated by murine epidermal cells but not hair follicle stem cells.
abstract: The spindle assembly checkpoint (SAC) ensures correct chromosome segregation during mitosis by preventing aneuploidy, an event that is detrimental to the fitness and survival of normal cells but oncogenic in tumor cells. Deletion of SAC genes is incompatible with early mouse development, and RNAi-mediated depletion of SAC components in cultured cells results in rapid death. Here we describe the use of a conditional KO of mouse Mad2, an essential component of the SAC signaling cascade, as a means to selectively induce chromosome instability and aneuploidy in the epidermis of the skin. We observe that SAC inactivation is tolerated by interfollicular epidermal cells but results in depletion of hair follicle bulge stem cells. Eventually, a histologically normal epidermis develops within ∼1 mo after birth, albeit without any hair. Mad2-deficient cells in this epidermis exhibited abnormal transcription of metabolic genes, consistent with aneuploid cell state. Hair follicle bulge stem cells were completely absent, despite the continued presence of rudimentary hair follicles. These data demonstrate that different cell lineages within a single tissue respond differently to chromosome instability: some proliferating cell lineages can survive, but stem cells are highly sensitive.
authors: Mouse Genomics, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom. f.foijer@umcg.nl
authors: Floris
authors: F
authors: Foijer
authors: Tia
authors: T
authors: DiTommaso
authors: Giacomo
authors: G
authors: Donati
authors: Katta
authors: K
authors: Hautaviita
authors: Stephanie Z
authors: SZ
authors: Xie
authors: Emma
authors: E
authors: Heath
authors: Ian
authors: I
authors: Smyth
authors: Fiona M
authors: FM
authors: Watt
authors: Peter K
authors: PK
authors: Sorger
authors: Allan
authors: A
authors: Bradley
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D002478:Cells, Cultured; D000078404:Epidermal Cells; D005434:Flow Cytometry; D006197:Hair / Q000166:cytology*; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D064246:Mad2 Proteins; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D034622:RNA Interference; D008941:Spindle Apparatus; D013234:Stem Cells / Q000166:cytology*
chemical_list: D018797:Cell Cycle Proteins; D064246:Mad2 Proteins; C577698:Mad2l1 protein, mouse
references: PLoS One. 2011;6(8):e23018
references: 21857983
references: Cell. 2011 Mar 4;144(5):646-74
references: 21376230
references: EMBO Mol Med. 2009 Aug;1(5):260-7
references: 20049729
references: Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8699-704
references: 15159543
references: Nat Cell Biol. 2007 Apr;9(4):461-9
references: 17351639
references: Biochim Biophys Acta. 2008 Sep;1786(1):73-82
references: 18706976
references: Semin Reprod Med. 2008 Sep;26(5):391-400
references: 18825607
references: Neurobiol Dis. 2009 May;34(2):212-20
references: 19344645
references: Bioinformatics. 2008 Jul 1;24(13):1547-8
references: 18467348
references: Nat Rev Mol Cell Biol. 2007 May;8(5):379-93
references: 17426725
references: Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12644-9
references: 22802626
references: Cell. 2011 Feb 18;144(4):499-512
references: 21315436
references: PLoS One. 2007 Jun 27;2(6):e558
references: 17593959
references: J Cell Physiol. 2010 Nov;225(2):310-5
references: 20568222
references: Environ Mol Mutagen. 1996;28(3):167-75
references: 8908177
references: Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W741-8
references: 15980575
references: Nucleic Acids Res. 2002 Feb 15;30(4):e15
references: 11842121
references: Science. 2008 Oct 31;322(5902):703-9
references: 18974345
references: Trends Genet. 2011 Nov;27(11):446-53
references: 21872963
references: Int J Cancer. 2013 May 15;132(10):2316-26
references: 23124507
references: Bioinformatics. 2002 Jan;18(1):207-8
references: 11836235
references: Nat Protoc. 2010 May;5(5):898-911
references: 20431535
references: Nat Rev Mol Cell Biol. 2009 Jul;10(7):478-87
references: 19546858
references: Nat Rev Cancer. 2010 Feb;10(2):102-15
references: 20094045
references: Cell. 2000 Jun 9;101(6):635-45
references: 10892650
references: Cell Stem Cell. 2007 Oct 11;1(4):371-81
references: 18371376
references: Curr Opin Cell Biol. 2005 Dec;17(6):583-9
references: 16226453
references: Nature. 2007 Mar 8;446(7132):185-9
references: 17330052
references: Nat Rev Mol Cell Biol. 2009 Mar;10(3):207-17
references: 19209183
references: Mutagenesis. 2008 Jan;23(1):57-65
references: 18048581
references: Science. 2007 Aug 17;317(5840):916-24
references: 17702937
references: Curr Opin Cell Biol. 2006 Dec;18(6):658-67
references: 17046232
references: Development. 2000 Nov;127(22):4775-85
references: 11044393