title: BCL9 is an essential component of canonical Wnt signaling that mediates the differentiation of myogenic progenitors during muscle regeneration.
abstract: Muscle stem cells and their progeny play a fundamental role in the regeneration of adult skeletal muscle. We have previously shown that activation of the canonical Wnt/beta-catenin signaling pathway in adult myogenic progenitors is required for their transition from rapidly dividing transient amplifying cells to more differentiated progenitors. Whereas Wnt signaling in Drosophila is dependent on the presence of the co-regulator Legless, previous studies of the mammalian ortholog of Legless, BCL9 (and its homolog, BCL9-2), have not revealed an essential role of these proteins in Wnt signaling in specific tissues during development. Using Cre-lox technology to delete BCL9 and BCL9-2 in the myogenic lineage in vivo and RNAi technology to knockdown the protein levels in vitro, we show that BCL9 is required for activation of the Wnt/beta-catenin cascade in adult mammalian myogenic progenitors. We observed that the nuclear localization of beta-catenin and downstream TCF/LEF-mediated transcription, which are normally observed in myogenic progenitors upon addition of exogenous Wnt and during muscle regeneration, were abrogated when BCL9/9-2 levels were reduced. Furthermore, reductions of BCL9/9-2 inhibited the promotion of myogenic differentiation by Wnt and the normal regenerative response of skeletal muscle. These results suggest a critical role of BCL9/9-2 in the Wnt-mediated regulation of adult, as opposed to embryonic, myogenic progenitors.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305-5235, USA. brack.andrew@mgh.harvard.edu
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Brack
authors.forename: Fabienne
authors.initials: F
authors.lastname: Murphy-Seiler
authors.forename: Jasmine
authors.initials: J
authors.lastname: Hanifi
authors.forename: Jürgen
authors.initials: J
authors.lastname: Deka
authors.forename: Sven
authors.initials: S
authors.lastname: Eyckerman
authors.forename: Charles
authors.initials: C
authors.lastname: Keller
authors.forename: Michel
authors.initials: M
authors.lastname: Aguet
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Rando
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage; D002478:Cells, Cultured; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D024510:Muscle Development / Q000502:physiology*; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012038:Regeneration / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D014157:Transcription Factors; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C111180:BCL9 protein, human; C545436:BCL9 protein, mouse; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; C453403:Lgs protein, Drosophila; D009363:Neoplasm Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin
references.citation: Curr Biol. 2005 Jul 12;15(13):1207-11
references.pmid: 16005293
references.citation: Genes Dev. 2005 Jun 15;19(12):1426-31
references.pmid: 15964993
references.citation: Genes Dev. 2008 Sep 1;22(17):2308-41
references.pmid: 18765787
references.citation: Development. 2004 Sep;131(17):4393-400
references.pmid: 15294866
references.citation: Development. 2002 Sep;129(17):4089-101
references.pmid: 12163411
references.citation: J Cell Biol. 1998 Sep 21;142(6):1447-59
references.pmid: 9744876
references.citation: Genes Dev. 1997 Aug 15;11(16):2040-51
references.pmid: 9284044
references.citation: Mol Biol Cell. 2004 Oct;15(10):4544-55
references.pmid: 15282335
references.citation: Mol Cell Biol. 2002 Feb;22(4):1172-83
references.pmid: 11809808
references.citation: Nat Cell Biol. 2002 May;4(5):367-73
references.pmid: 11988739
references.citation: Genesis. 2007 May;45(5):318-25
references.pmid: 17458864
references.citation: Cancer Cell. 2007 Apr;11(4):375-88
references.pmid: 17418413
references.citation: Cell. 2006 Nov 3;127(3):469-80
references.pmid: 17081971
references.citation: Genes Dev. 2004 Sep 15;18(18):2225-30
references.pmid: 15371335
references.citation: Development. 2002 Jun;129(11):2565-76
references.pmid: 12015286
references.citation: Curr Biol. 2007 Mar 20;17(6):556-61
references.pmid: 17320388
references.citation: Mol Cell Biol. 2008 May;28(10):3526-37
references.pmid: 18347063
references.citation: Mol Cell. 2008 May 23;30(4):507-18
references.pmid: 18498752
references.citation: J Bone Miner Res. 2007 Dec;22(12):1913-23
references.pmid: 17696762
references.citation: EMBO J. 1999 Dec 15;18(24):6867-72
references.pmid: 10601008
references.citation: J Cell Sci. 2008 May 1;121(Pt 9):1373-82
references.pmid: 18397993
references.citation: Development. 1998 Nov;125(21):4155-62
references.pmid: 9753670
references.citation: Development. 2003 Aug;130(15):3503-14
references.pmid: 12810597
references.citation: J Cell Biol. 2004 Aug 2;166(3):347-57
references.pmid: 15277541
references.citation: BMC Cell Biol. 2006 Jul 06;7:28
references.pmid: 16824228
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9685-90
references.pmid: 17522258
references.citation: Dev Biol. 2001 Nov 1;239(1):79-94
references.pmid: 11784020
references.citation: Science. 2007 Aug 10;317(5839):807-10
references.pmid: 17690295
references.citation: Development. 2007 May;134(10):1873-85
references.pmid: 17428831
references.citation: BMC Biol. 2007 Apr 10;5:15
references.pmid: 17425782
references.citation: J Neurosci. 2007 Apr 11;27(15):4210-9
references.pmid: 17428999
references.citation: Cell. 2002 Apr 5;109(1):47-60
references.pmid: 11955446
references.citation: Dev Biol. 2007 Apr 15;304(2):604-14
references.pmid: 17275805
references.citation: Mech Dev. 2005 Nov;122(11):1171-82
references.pmid: 16169192
references.citation: Dev Biol. 1997 Nov 15;191(2):270-83
references.pmid: 9398440
references.citation: Genes Dev. 2006 Sep 1;20(17):2450-64
references.pmid: 16951257
references.citation: Development. 2006 Sep;133(18):3723-32
references.pmid: 16936075
references.citation: Cell Stem Cell. 2008 Jan 10;2(1):50-9
references.pmid: 18371421
references.citation: Nat Cell Biol. 2004 Jul;6(7):626-33
references.pmid: 15208637
references.citation: Mech Dev. 2007 Jan;124(1):59-67
references.pmid: 17113272
references.citation: Proc Natl Acad Sci U S A. 2008 May 6;105(18):6644-9
references.pmid: 18451032
references.citation: Nat Genet. 1999 Jan;21(1):70-1
references.pmid: 9916792
references.citation: Annu Rev Cell Dev Biol. 2004;20:781-810
references.pmid: 15473860
references.citation: Cell. 2007 Jun 1;129(5):999-1010
references.pmid: 17540178
references.citation: Clin Cancer Res. 2007 Jul 15;13(14):4042-5
references.pmid: 17634527