title: Neutral competition of stem cells is skewed by proliferative changes downstream of Hh and Hpo.
abstract: Neutral competition, an emerging feature of stem cell homeostasis, posits that individual stem cells can be lost and replaced by their neighbors stochastically, resulting in chance dominance of a clone at the niche. A single stem cell with an oncogenic mutation could bias this process and clonally spread the mutation throughout the stem cell pool. The Drosophila testis provides an ideal system for testing this model. The niche supports two stem cell populations that compete for niche occupancy. Here, we show that cyst stem cells (CySCs) conform to the paradigm of neutral competition and that clonal deregulation of either the Hedgehog (Hh) or Hippo (Hpo) pathway allows a single CySC to colonize the niche. We find that the driving force behind such behavior is accelerated proliferation. Our results demonstrate that a single stem cell colonizes its niche through oncogenic mutation by co-opting an underlying homeostatic process.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA marc.amoyel@nyumc.org erika.bach@nyu.edu.
authors.forename: Marc
authors.initials: M
authors.lastname: Amoyel
authors.affiliation: Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK Wellcome Trust-CRUK Gurdon Institute, University of Cambridge, Cambridge, UK Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Simons
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, New York University School of Medicine, New York, NY, USA marc.amoyel@nyumc.org erika.bach@nyu.edu.
authors.forename: Erika A
authors.initials: EA
authors.lastname: Bach
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002999:Clone Cells; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008962:Models, Theoretical; D009154:Mutation; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics*; D015398:Signal Transduction; D055153:Stem Cell Niche / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D013737:Testis / Q000166:cytology / Q000378:metabolism; D000099317:Hippo Kinases
chemical_list: D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D011956:Receptors, Cell Surface; C070844:ptc protein, Drosophila; C077245:hh protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases
keywords: Hedgehog; Hippo; competition; stem cell; testis
references.citation: Dev Cell. 2010 Oct 19;19(4):491-505
references.pmid: 20951342
references.citation: Nat Cell Biol. 2006 Jun;8(6):601-6
references.pmid: 16648844
references.citation: Cell. 2010 Oct 1;143(1):134-44
references.pmid: 20887898
references.citation: J Cell Biol. 2008 Feb 25;180(4):721-8
references.pmid: 18283115
references.citation: Nature. 2014 Mar 20;507(7492):362-365
references.pmid: 24531760
references.citation: Aging Cell. 2006 Aug;5(4):297-304
references.pmid: 16800845
references.citation: Nat Cell Biol. 2007 Dec;9(12):1413-8
references.pmid: 17982446
references.citation: Cell. 2001 May 4;105(3):357-68
references.pmid: 11348592
references.citation: Science. 2010 Nov 5;330(6005):822-5
references.pmid: 20929733
references.citation: Development. 2011 Dec;138(23):5079-86
references.pmid: 22031544
references.citation: Science. 2012 Aug 31;337(6098):1091-3
references.pmid: 22821983
references.citation: Nat Cell Biol. 2006 Jan;8(1):27-36
references.pmid: 16341207
references.citation: Neuron. 1999 Mar;22(3):451-61
references.pmid: 10197526
references.citation: Development. 2011 Jul;138(14):2861-9
references.pmid: 21693509
references.citation: Science. 2007 Jan 26;315(5811):518-21
references.pmid: 17255513
references.citation: Cell. 2012 Jun 8;149(6):1179-81
references.pmid: 22682238
references.citation: Dev Cell. 2010 Apr 20;18(4):556-68
references.pmid: 20412771
references.citation: Development. 2011 May;138(9):1687-96
references.pmid: 21486923
references.citation: Development. 1999 Oct;126(19):4331-9
references.pmid: 10477300
references.citation: Cell. 2004 Apr 2;117(1):117-29
references.pmid: 15066287
references.citation: J Cell Sci. 2012 Jan 1;125(Pt 1):233-45
references.pmid: 22266901
references.citation: J Cell Physiol. 2010 May;223(2):500-10
references.pmid: 20143337
references.citation: Curr Biol. 2007 Jan 23;17(2):165-72
references.pmid: 17196391
references.citation: Genes Dev. 1995 Jun 15;9(12):1445-55
references.pmid: 7601349
references.citation: Cell. 2001 May 4;105(3):345-55
references.pmid: 11348591
references.citation: Cell. 1998 Jul 24;94(2):251-60
references.pmid: 9695953
references.citation: EMBO Rep. 2014 Jan;15(1):62-9
references.pmid: 24355609
references.citation: Dev Biol. 1975 Feb;42(2):211-21
references.pmid: 1116643
references.citation: Nature. 2008 Aug 28;454(7208):1132-6
references.pmid: 18641633
references.citation: Nature. 2001 Mar 29;410(6828):599-604
references.pmid: 11279500
references.citation: Development. 2004 Mar;131(6):1365-75
references.pmid: 14973292
references.citation: EMBO J. 1990 Nov;9(11):3573-81
references.pmid: 2120045
references.citation: Cell. 1989 Apr 7;57(1):177-87
references.pmid: 2702688
references.citation: Curr Opin Cell Biol. 2010 Dec;22(6):730-6
references.pmid: 20817500
references.citation: EMBO J. 1996 Dec 2;15(23):6584-94
references.pmid: 8978685
references.citation: Science. 2001 Dec 21;294(5551):2542-5
references.pmid: 11752574
references.citation: Development. 2012 Aug;139(15):2663-9
references.pmid: 22745310
references.citation: Cell. 2007 Sep 21;130(6):1120-33
references.pmid: 17889654
references.citation: EMBO J. 2012 May 30;31(11):2473-85
references.pmid: 22522699
references.citation: Nature. 2009 Apr 9;458(7239):776-9
references.pmid: 19169242
references.citation: Science. 2003 Sep 12;301(5639):1547-50
references.pmid: 12970569
references.citation: Genes Dev. 1999 Dec 15;13(24):3244-58
references.pmid: 10617573
references.citation: Dev Dyn. 2008 Jan;237(1):270-5
references.pmid: 18095349
references.citation: Science. 1999 Sep 24;285(5436):2126-9
references.pmid: 10497130
references.citation: Development. 1995 Nov;121(11):3797-807
references.pmid: 8582289
references.citation: Cell Stem Cell. 2008 Jul 3;3(1):44-54
references.pmid: 18593558
references.citation: Development. 2013 Jan 1;140(1):56-65
references.pmid: 23175633
references.citation: Science. 2000 Oct 13;290(5490):328-30
references.pmid: 11030649
references.citation: J Ultrastruct Res. 1979 Nov;69(2):180-90
references.pmid: 114676
references.citation: Nature. 2007 Mar 8;446(7132):185-9
references.pmid: 17330052
references.citation: Nat Cell Biol. 2010 Aug;12(8):806-11
references.pmid: 20622868
references.citation: Development. 2008 Mar;135(6):1081-8
references.pmid: 18256197
references.citation: Science. 2001 Dec 21;294(5551):2546-9
references.pmid: 11752575
references.citation: Nature. 2001 Nov 1;414(6859):105-11
references.pmid: 11689955
references.citation: Cell Mol Bioeng. 2013 Dec;6(4):441-448
references.pmid: 24465278
references.citation: Cell Stem Cell. 2010 Aug 6;7(2):214-24
references.pmid: 20682447
references.citation: Nat Cell Biol. 1999 Dec;1(8):500-6
references.pmid: 10587646
references.citation: Science. 2009 Oct 2;326(5949):153-6
references.pmid: 19797664
references.citation: Curr Biol. 2003 Jan 8;13(1):53-8
references.pmid: 12526745
references.citation: Development. 2011 Mar;138(5):831-7
references.pmid: 21303845
references.citation: Cell. 1998 Jun 26;93(7):1183-93
references.pmid: 9657151
references.citation: Curr Biol. 2003 Dec 2;13(23):2065-72
references.pmid: 14653996
references.citation: Bull Math Biol. 2012 May;74(5):1207-25
references.pmid: 22231521
references.citation: Cell. 2011 Jun 10;145(6):851-62
references.pmid: 21663791
references.citation: Cell Stem Cell. 2007 Sep 13;1(3):277-85
references.pmid: 18371362
references.citation: Development. 2014 Mar;141(5):988-1000
references.pmid: 24550108
references.citation: Cell. 1996 Nov 1;87(3):553-63
references.pmid: 8898207
references.citation: Genes Dev. 2002 Feb 1;16(3):388-98
references.pmid: 11825879
references.citation: Science. 2013 Nov 22;342(6161):995-8
references.pmid: 24264992
references.citation: Cell. 2004 Apr 2;117(1):107-16
references.pmid: 15066286
references.citation: Development. 1996 Apr;122(4):1125-35
references.pmid: 8620839
references.citation: Endocrinology. 1996 Mar;137(3):846-56
references.pmid: 8603594
references.citation: Development. 2011 Aug;138(16):3367-76
references.pmid: 21752931
references.citation: Cell Stem Cell. 2008 Jan 10;2(1):39-49
references.pmid: 18371420
references.citation: Nat Cell Biol. 2012 Dec;14(12):1282-94
references.pmid: 23178882
references.citation: Nature. 1991 Sep 12;353(6340):184-7
references.pmid: 1653906