title: Tbx2 terminates shh/fgf signaling in the developing mouse limb bud by direct repression of gremlin1.
abstract: Vertebrate limb outgrowth is driven by a positive feedback loop that involves Sonic hedgehog (Shh) and Gremlin1 (Grem1) in the posterior limb bud mesenchyme and Fibroblast growth factors (Fgfs) in the overlying epithelium. Proper spatio-temporal control of these signaling activities is required to avoid limb malformations such as polydactyly. Here we show that, in Tbx2-deficient hindlimbs, Shh/Fgf4 signaling is prolonged, resulting in increased limb bud size and duplication of digit 4. In turn, limb-specific Tbx2 overexpression leads to premature termination of this signaling loop with smaller limbs and reduced digit number as phenotypic manifestation. We show that Tbx2 directly represses Grem1 in distal regions of the posterior limb mesenchyme allowing Bone morphogenetic protein (Bmp) signaling to abrogate Fgf4/9/17 expression in the overlying epithelium. Since Tbx2 itself is a target of Bmp signaling, our data identify a growth-inhibiting positive feedback loop (Bmp/Tbx2/Grem1). We propose that proliferative expansion of Tbx2-expressing cells mediates self-termination of limb bud outgrowth due to their refractoriness to Grem1 induction.
authors: Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, Germany.
authors: Henner F
authors: HF
authors: Farin
authors: Timo H-W
authors: TH
authors: Lüdtke
authors: Martina K
authors: MK
authors: Schmidt
authors: Susann
authors: S
authors: Placzko
authors: Karin
authors: K
authors: Schuster-Gossler
authors: Marianne
authors: M
authors: Petry
authors: Vincent M
authors: VM
authors: Christoffels
authors: Andreas
authors: A
authors: Kispert
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D016207:Cytokines; D004848:Epithelium / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D018878:Limb Buds / Q000254:growth & development* / Q000378:metabolism; D008648:Mesoderm / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D010641:Phenotype; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D016207:Cytokines; D005346:Fibroblast Growth Factors; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D020825:T-Box Domain Proteins; C113178:Grem1 protein, mouse; C465570:Shh protein, mouse; C097348:T-Box Domain Protein 2
references: EMBO J. 2002 Mar 1;21(5):966-75
references: 11867524
references: Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18604-9
references: 19846762
references: Development. 2005 Apr;132(8):1961-70
references: 15790970
references: Circ Res. 2009 Jun 5;104(11):1267-74
references: 19423846
references: Development. 2006 Feb;133(4):663-73
references: 16421190
references: Nature. 1994 Oct 13;371(6498):609-12
references: 7935794
references: Dev Cell. 2009 Apr;16(4):600-6
references: 19386268
references: Nature. 2002 Aug 1;418(6897):501-8
references: 12152071
references: Science. 2004 Jul 16;305(5682):396-9
references: 15256670
references: Cell. 1994 Dec 16;79(6):993-1003
references: 8001146
references: PLoS Genet. 2013;9(1):e1003189
references: 23341776
references: Development. 2005 Dec;132(24):5601-11
references: 16314491
references: Genes Dev. 1996 Feb 1;10(3):301-12
references: 8595881
references: Nat Genet. 2003 Jul;34(3):303-7
references: 12808456
references: Dev Cell. 2008 Apr;14(4):624-32
references: 18410737
references: Nat Chem Biol. 2008 Jan;4(1):33-41
references: 18026094
references: PLoS Genet. 2006 Dec;2(12):e216
references: 17194222
references: Dev Biol. 2009 Dec 15;336(2):145-55
references: 19769959
references: Development. 2004 Oct;131(20):5041-52
references: 15459098
references: Dev Biol. 2001 Aug 15;236(2):421-35
references: 11476582
references: Nature. 1999 Oct 7;401(6753):598-602
references: 10524628
references: Methods Enzymol. 1993;225:361-73
references: 8231863
references: Development. 2001 Nov;128(22):4463-74
references: 11714672
references: Mech Dev. 1997 Feb;62(1):67-78
references: 9106168
references: J Embryol Exp Morphol. 1974 Dec;32(3):651-60
references: 4463222
references: Development. 2005 Oct;132(19):4235-45
references: 16120640
references: Development. 1998 Jul;125(13):2499-509
references: 9609833
references: Mech Dev. 1999 Mar;81(1-2):205-8
references: 10330501
references: BMC Dev Biol. 2006 Dec 15;6:62
references: 17173667
references: Genesis. 2002 Jun;33(2):77-80
references: 12112875
references: Circ Res. 2009 Aug 28;105(5):442-52
references: 19661464
references: Development. 1999 Oct;126(20):4465-75
references: 10498682
references: Science. 2009 Feb 20;323(5917):1050-3
references: 19229034
references: Dev Biol. 2006 Nov 1;299(1):12-21
references: 16989805
references: Dev Cell. 2001 Sep;1(3):423-34
references: 11702953
references: Genes Dev. 2008 Oct 1;22(19):2651-63
references: 18832070
references: Nature. 2008 Jul 31;454(7204):638-41
references: 18594511
references: Cell. 2004 Aug 20;118(4):517-28
references: 15315763
references: Dev Biol. 2004 Dec 15;276(2):268-79
references: 15581864
references: Nat Rev Genet. 2009 Dec;10(12):845-58
references: 19920852
references: Genesis. 2000 Nov-Dec;28(3-4):147-55
references: 11105057
references: Development. 2004 Jul;131(14):3401-10
references: 15201225
references: Dev Dyn. 1996 Aug;206(4):379-90
references: 8853987
references: Nature. 2008 May 15;453(7193):401-5
references: 18449196
references: Cell Mol Life Sci. 2012 Apr;69(8):1377-89
references: 22130515
references: Am J Med Genet. 1999 Sep 17;86(3):278-81
references: 10482880
references: J Histochem Cytochem. 2001 Jan;49(1):1-8
references: 11118473
references: Nat Genet. 1999 Jan;21(1):70-1
references: 9916792
references: Nat Genet. 1995 Jan;9(1):15-20
references: 7704017
references: Curr Biol. 2001 Apr 3;11(7):503-7
references: 11413000
references: Dev Cell. 2012 Apr 17;22(4):837-48
references: 22465667
references: Mol Cell Biol. 1998 Sep;18(9):5099-108
references: 9710594
references: Development. 2003 May;130(10):2263-73
references: 12668638
references: Dev Cell. 2004 Jan;6(1):43-53
references: 14723846
references: Dev Dyn. 2001 Apr;220(4):295-306
references: 11307164
references: Orphanet J Rare Dis. 2012 Jan 11;7:4
references: 22236771
references: Genes Dev. 2004 May 15;18(10):1209-21
references: 15155583
references: Dev Biol. 2007 Apr 1;304(1):9-21
references: 17300775