title: Lgr4 and Lgr5 drive the formation of long actin-rich cytoneme-like membrane protrusions.
abstract: Embryonic development and adult tissue homeostasis require precise information exchange between cells and their microenvironment to coordinate cell behavior. A specialized class of ultra-long actin-rich filopodia, termed cytonemes, provides one mechanism for this spatiotemporal regulation of extracellular cues. We provide here a mechanism whereby the stem-cell marker Lgr5, and its family member Lgr4, promote the formation of cytonemes. Lgr4- and Lgr5-induced cytonemes exceed lengths of 80 µm, are generated through stabilization of nascent filopodia from an underlying lamellipodial-like network and functionally provide a pipeline for the transit of signaling effectors. As proof-of-principle, we demonstrate that Lgr5-induced cytonemes act as conduits for cell signaling by demonstrating that the actin motor and filopodial cargo carrier protein myosin X (Myo10) and the G-protein-coupled receptor (GPCR) signaling effector β-arrestin-2 (Arrb2) transit into cytonemes. This work delineates a biological function for Lgr4 and Lgr5 and provides the rationale to fully investigate Lgr4 and Lgr5 function and cytonemes in mammalian stem cell and cancer stem cell behavior.
authors: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors: Joshua C
authors: JC
authors: Snyder
authors: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors: Lauren K
authors: LK
authors: Rochelle
authors: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors: Sébastien
authors: S
authors: Marion
authors: Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors: H Kim
authors: HK
authors: Lyerly
authors: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors: Larry S
authors: LS
authors: Barak
authors: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA marc.caron@dm.duke.edu.
authors: Marc G
authors: MG
authors: Caron
mesh_terms: D000199:Actins / Q000378:metabolism*; D000328:Adult; D019390:Arrestins / Q000378:metabolism; D001692:Biological Transport; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism*; D022081:Cell Surface Extensions / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D011554:Pseudopodia / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; D000199:Actins; D019390:Arrestins; C411562:LGR4 protein, human; C116884:LGR5 protein, human; D043562:Receptors, G-Protein-Coupled; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
keywords: Cytoneme; GPCR; Lgr5; Stem cell
references: Nature. 2013 Feb 14;494(7436):247-50
references: 23354049
references: PLoS Biol. 2012;10(4):e1001298
references: 22509132
references: J Cell Biol. 2000 Aug 21;150(4):807-22
references: 10953005
references: Cell Rep. 2013 Jan 31;3(1):70-8
references: 23352663
references: Proc Natl Acad Sci U S A. 2014 Apr 1;111(13):E1221-9
references: 24639526
references: Invest Ophthalmol Vis Sci. 2008 Oct;49(10):4245-53
references: 18487371
references: Development. 2014 Feb;141(4):729-36
references: 24496611
references: Biophys J. 2005 Aug;89(2):782-95
references: 15879474
references: EMBO Rep. 2013 Aug;14(8):726-32
references: 23817552
references: Cell. 1999 May 28;97(5):599-607
references: 10367889
references: J Biol Chem. 2013 Apr 12;288(15):10286-97
references: 23439653
references: Exp Cell Res. 1963 Dec;32:570-89
references: 14099826
references: Nature. 2009 Apr 23;458(7241):1025-9
references: 19295515
references: Science. 2014 Feb 21;343(6173):1244624
references: 24385607
references: J Biol Chem. 2007 Jun 29;282(26):18937-44
references: 17456469
references: Nature. 2011 Jul 04;476(7360):293-7
references: 21727895
references: Br J Cancer. 2014 Jul 29;111(3):539-50
references: 24921915
references: J Cell Biol. 2003 Feb 3;160(3):409-21
references: 12566431
references: J Cell Biol. 2010 May 3;189(3):541-56
references: 20421424
references: J Biol Chem. 2014 Aug 22;289(34):23809-16
references: 24966324
references: Nat Genet. 2008 Nov;40(11):1291-9
references: 18849992
references: Traffic. 2010 Oct;11(10):1265-71
references: 20477987
references: Mol Endocrinol. 1998 Dec;12(12):1830-45
references: 9849958
references: PLoS One. 2013 Dec 27;8(12):e84476
references: 24386388
references: Nature. 2009 Jan 29;457(7229):608-11
references: 19092804
references: Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11452-7
references: 21693646
references: Nat Cell Biol. 2007 Dec;9(12):1360-9
references: 18026092
references: Science. 2011 Apr 15;332(6027):354-8
references: 21493861
references: J Clin Invest. 2014 Mar;124(3):1069-82
references: 24487586
references: Curr Protoc Immunol. 2001 May;Chapter 10:Unit 10.13
references: 18432676
references: Nat Rev Drug Discov. 2010 May;9(5):373-86
references: 20431569
references: J Cell Sci. 2013 May 1;126(Pt 9):2060-8
references: 23444378
references: J Biol Chem. 2014 Sep 19;289(38):26492-26504
references: 25063812
references: Mol Endocrinol. 2000 Aug;14(8):1257-71
references: 10935549
references: Curr Biol. 2014 Jun 2;24(11):1199-211
references: 24814146
references: Nat Rev Mol Cell Biol. 2006 Apr;7(4):296-302
references: 16482093
references: Nature. 2005 Sep 22;437(7058):560-3
references: 16177792
references: Nat Cell Biol. 2002 Mar;4(3):246-50
references: 11854753
references: Science. 2012 Aug 10;337(6095):730-5
references: 22855427
references: J Pathol. 2012 Nov;228(3):300-9
references: 22926799
references: Trends Cell Biol. 2007 Mar;17(3):107-17
references: 17275303
references: EMBO J. 2013 Oct 16;32(20):2708-21
references: 24045232
references: Oncogene. 1998 Jul 30;17(4):503-10
references: 9696044
references: Science. 2011 Apr 15;332(6027):312-3
references: 21493848
references: Nature. 2007 Oct 25;449(7165):1003-7
references: 17934449
references: Science. 2010 Mar 12;327(5971):1385-9
references: 20223988
references: Nat Cell Biol. 2004 Jun;6(6):523-31
references: 15156152
references: J Exp Zool. 1989 Aug;251(2):167-85
references: 2549171
references: J Cell Biol. 2007 Jun 4;177(5):829-41
references: 17548511
references: Cell Motil Cytoskeleton. 1992;22(3):160-9
references: 1423662
references: Dev Biol. 2014 Jun 15;390(2):181-90
references: 24680895
references: Mol Cell Biol. 2012 Jun;32(11):2054-64
references: 22473993
references: Development. 1995 Aug;121(8):2501-11
references: 7671814
references: Mol Biol Cell. 2008 Apr;19(4):1561-74
references: 18256280
references: J Biol Chem. 1997 Oct 31;272(44):27497-500
references: 9346876
references: Development. 2014 Jun;141(11):2206-15
references: 24821987
references: Cell Rep. 2012 Sep 27;2(3):540-52
references: 22999937
references: Cell. 2004 Aug 6;118(3):363-73
references: 15294161
references: Cell Stem Cell. 2010 Jan 8;6(1):25-36
references: 20085740