title: Wnt-frizzled signaling is part of an FGF-induced cascade that promotes lens fiber differentiation.
abstract: OBJECTIVE
  It is well established that lens fiber differentiation depends on an FGF-initiated growth factor signaling cascade. Given that recent studies indicate Wnt-Frizzled/Planar Cell Polarity (Wnt-Fz/PCP) signaling has a role in coordinating the orientation and alignment of fibers, this study set out to investigate the relationship between this pathway and FGF-induced fiber differentiation.
  
  
  METHODS
  Rat lens epithelial explants were cultured with FGF-2. Regulators of Wnt-Fz signaling, secreted frizzled-related protein-1 (Sfrp1), and inhibitor of Wnt production-2 (IWP-2) were applied to assess the role of this pathway in FGF-induced fiber differentiation. A TCF/Lef reporter mouse was used to assess canonical Wnt-Fz/β-catenin signaling.
  
  
  RESULTS
  FGF-induced fiber differentiation was accompanied by upregulation of Wnt-Fz signaling components, Fz3, Fz6, Dishevelled-2 (Dvl2), and Dishevelled-3. During differentiation, Fz and the centrosome/primary cilium translocated to the apical tip/leading edge of similarly polarized groups of cells. Addition of Sfrp1 or IWP-2 to FGF-treated explants inhibited cell elongation and reduced expression of fiber-specific markers, filensin and β-crystallin. Expression of Wnt-Fz signaling components was also reduced and a significant reduction in the active form of Dvl2 indicated inhibition of the pathway. Analysis of the TCF/Lef reporter mouse showed no evidence of canonical Wnt-Fz/β-catenin signaling during FGF-induced fiber differentiation.
  
  
  CONCLUSIONS
  This study shows that Wnt-Fz signaling is a component of the FGF-initiated cascade that regulates fiber differentiation. The presence of groups of fibers with Fz and centrosome/primary cilium polarized to the leading edge of each cell is consistent with a role for noncanonical Wnt-Fz signaling in coordinating polarized behavior of differentiating fibers.
authors: Save Sight Institute, University of Sydney, Sydney, New South Wales, Australia.
authors: Lucy J
authors: LJ
authors: Dawes
authors: Yuki
authors: Y
authors: Sugiyama
authors: Ana S
authors: AS
authors: Tanedo
authors: Frank J
authors: FJ
authors: Lovicu
authors: John W
authors: JW
authors: McAvoy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D000072261:Dishevelled Proteins; D005136:Eye Proteins / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D051157:Frizzled Receptors / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000378:metabolism; D007908:Lens, Crystalline / Q000166:cytology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology; D051153:Wnt Proteins / Q000502:physiology*; D038204:beta-Crystallins / Q000378:metabolism; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; D005136:Eye Proteins; D016222:Fibroblast Growth Factor 2; D051157:Frizzled Receptors; D036341:Intercellular Signaling Peptides and Proteins; D007381:Intermediate Filament Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D051153:Wnt Proteins; D038204:beta-Crystallins; C000606582:Dvl2 protein, mouse; C000606585:Dvl3 protein, mouse; C486339:Fzd3 protein, mouse; C500646:Sfrp1 protein, rat; D000094742:Secreted Frizzled-Related Proteins; C079098:filensin
references: Mech Dev. 2000 Mar 1;91(1-2):427-31
references: 10704878
references: Dev Biol. 2005 Sep 15;285(2):477-89
references: 16102745
references: Sci Signal. 2011 Jan 25;4(157):ra4
references: 21266715
references: Dev Biol. 2009 Jun 1;330(1):44-53
references: 19306866
references: Development. 2012 Nov;139(22):4220-31
references: 23034628
references: J Embryol Exp Morphol. 1978 Jun;45:271-81
references: 353215
references: Genesis. 2007 Apr;45(4):157-68
references: 17410548
references: Dev Biol. 2009 Aug 1;332(1):166-76
references: 19481073
references: Semin Cell Dev Biol. 2006 Dec;17(6):726-40
references: 17116415
references: Development. 1989 Oct;107(2):221-8
references: 2632221
references: Exp Eye Res. 1989 Sep;49(3):479-94
references: 2792239
references: Curr Top Dev Biol. 2008;85:261-301
references: 19147009
references: Dev Biol. 2008 Jun 15;318(2):276-88
references: 18455718
references: BMC Dev Biol. 2006 Mar 15;6:14
references: 16539717
references: Development. 1995 Feb;121(2):505-14
references: 7539358
references: Development. 2004 Apr;131(8):1813-24
references: 15084465
references: BMC Dev Biol. 2002 Jul 02;2:8
references: 12095419
references: Dev Cell. 2011 Jul 19;21(1):120-33
references: 21763613
references: Dev Biol. 2011 Jul 1;355(1):12-20
references: 21536023
references: J Biol Chem. 2005 Jan 7;280(1):777-86
references: 15509575
references: EMBO J. 2010 Apr 7;29(7):1192-204
references: 20224554
references: J Biol Chem. 1999 Jun 4;274(23):16180-7
references: 10347172
references: Dev Biol. 2008 Sep 15;321(2):420-33
references: 18652817
references: Development. 2009 Jan;136(1):23-8
references: 19036800
references: Int J Dev Biol. 2004;48(8-9):889-902
references: 15558480
references: Dev Biol. 2005 Apr 1;280(1):1-14
references: 15766743
references: Organogenesis. 2011 Jul-Sep;7(3):191-201
references: 22027540
references: Dev Growth Differ. 2011 Oct;53(8):911-23
references: 21995331
references: Exp Eye Res. 2004 Apr;78(4):875-89
references: 15037121
references: Dev Biol. 2010 Feb 15;338(2):193-201
references: 19968984
references: Cell. 2012 Jun 8;149(6):1192-205
references: 22682243
references: J Biol Chem. 2004 Jul 23;279(30):31813-22
references: 15145928
references: Oncogene. 2006 Dec 4;25(57):7505-11
references: 17143294
references: Curr Top Dev Biol. 2006;72:153-66
references: 16564334
references: Mol Cell Biol. 2004 Jun;24(11):4757-68
references: 15143170
references: Dev Biol. 2003 Jul 1;259(1):48-61
references: 12812787
references: J Embryol Exp Morphol. 1978 Apr;44:149-65
references: 650132
references: Development. 2006 Aug;133(16):3167-77
references: 16854977
references: Nat Chem Biol. 2009 Feb;5(2):100-7
references: 19125156
references: Dev Dyn. 2004 Oct;231(2):416-24
references: 15366019
references: Invest Ophthalmol Vis Sci. 2006 Nov;47(11):5088-97
references: 17065530
references: Cold Spring Harb Perspect Biol. 2012 May 01;4(5):
references: 22550229
references: Dev Biol. 2008 Dec 1;324(1):161-76
references: 18824165
references: Nat Genet. 2008 Jul;40(7):871-9
references: 18552847
references: Dev Dyn. 2003 Jul;227(3):323-34
references: 12815618
references: Dev Biol. 2007 Aug 1;308(1):54-67
references: 17574231