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PMID: 12502739 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

FGF4, a direct target of LEF1 and Wnt signaling, can rescue the arrest of tooth organogenesis in Lef1(-/-) mice.

Genes & development ·Vol. 16 ·No. 24 ·2002-12-15 ·Pages 3173-85

Kratochwil K, Galceran J, Tontsch S, Roth W, Grosschedl R

Abstract

Lymphoid enhancer factor (LEF1), a nuclear mediator of Wnt signaling, is required for the formation of organs that depend on inductive interactions between epithelial and mesenchymal tissues. In previous tissue recombination experiments with normal and Lef1(-/-) tooth germs, we found that the effect of LEF1 expression in the epithelium is tissue nonautonomous and transferred to the subjacent mesenchyme. Here we examine the molecular basis for LEF1 function and find that the epithelium of the developmentally arrested Lef1(-/-) tooth rudiments fails to express Fgf4, Shh, and Bmp4, but not Wnt10a. We identify the Fgf4 gene as a direct transcriptional target for LEF1 and show that beads soaked with recombinant FGF4 protein can fully overcome the developmental arrest of Lef1(-/-) tooth germs. In addition, we find that FGF4 beads induce rapidly the expression of Fgf3 in dental mesenchyme and that both epithelial and mesenchymal FGF proteins induce the delayed expression of Shh in the epithelium. Taken together, these data indicate that a single target of LEF1 can account for the function of LEF1 in tooth development and for a relay of a Wnt signal reception to a cascade of FGF signaling activities, allowing for a sequential and reciprocal communication between epithelium and mesenchyme.

MeSH Terms
Animals Bone Morphogenetic Protein 4 Bone Morphogenetic Proteins/genetics,metabolism Cell Differentiation Cytoskeletal Proteins/metabolism DNA-Binding Proteins/physiology Electrophoretic Mobility Shift Assay Embryonic Induction Epithelial Cells/physiology Fibroblast Growth Factor 4 Fibroblast Growth Factors/metabolism Gene Expression Gene Expression Regulation, Developmental/physiology Hedgehog Proteins Lymphoid Enhancer-Binding Factor 1 Mesoderm/physiology Mice Mice, Inbred C57BL Mice, Mutant Strains Odontogenesis Proto-Oncogene Proteins/metabolism Recombinant Proteins/metabolism Signal Transduction Tooth/embryology Trans-Activators/genetics,metabolism Transcription Factors/physiology Wnt Proteins Zebrafish Proteins beta Catenin
Chemicals
Bmp4 protein, mouse Bone Morphogenetic Protein 4 Bone Morphogenetic Proteins CTNNB1 protein, mouse Cytoskeletal Proteins DNA-Binding Proteins Fgf4 protein, mouse Fibroblast Growth Factor 4 Hedgehog Proteins Lef1 protein, mouse Lymphoid Enhancer-Binding Factor 1 Proto-Oncogene Proteins Recombinant Proteins Trans-Activators Transcription Factors Wnt Proteins Zebrafish Proteins beta Catenin bmp4 protein, zebrafish Fibroblast Growth Factors
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Kratochwil Klaus
Institute of Molecular Biology, Austrian Academy of Sciences, 5020 Salzburg, Austria.
Galceran Juan
Tontsch Sabine
Roth Wera
Grosschedl Rudolf
References (70)
70 references, click to expand
  1. The enamel knot as a signaling center in the developing mouse tooth.
    Mech Dev. 1996 Jan;54(1):39-43 PMID: 8808404
  2. Engrailed-1 as a target of the Wnt-1 signalling pathway in vertebrate midbrain development.
    Nature. 1996 Sep 26;383(6598):332-4 PMID: 8848044
  3. Nuclear localization of beta-catenin by interaction with transcription factor LEF-1.
    Mech Dev. 1996 Sep;59(1):3-10 PMID: 8892228
  4. LEF-1, a nuclear factor coordinating signaling inputs from wingless and decapentaplegic.
    Cell. 1997 Mar 21;88(6):777-87 PMID: 9118221
  5. Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors.
    Science. 1997 May 9;276(5314):955-60 PMID: 9139660
  6. Activation of the Wnt signaling pathway: a molecular mechanism for lithium action.
    Dev Biol. 1997 May 1;185(1):82-91 PMID: 9169052
  7. The Wnt/beta-catenin pathway posteriorizes neural tissue in Xenopus by an indirect mechanism requiring FGF signalling.
    Dev Biol. 2001 Nov 1;239(1):148-60 PMID: 11784025
  8. TCF transcription factors, mediators of Wnt-signaling in development and cancer.
    Dev Biol. 2002 Apr 1;244(1):1-8 PMID: 11900454
  9. Getting under the skin of epidermal morphogenesis.
    Nat Rev Genet. 2002 Mar;3(3):199-209 PMID: 11972157
  10. Regulation of hair follicle development by the TNF signal ectodysplasin and its receptor Edar.
    Development. 2002 May;129(10):2541-53 PMID: 11973284
  11. WNT signals are required for the initiation of hair follicle development.
    Dev Cell. 2002 May;2(5):643-53 PMID: 12015971
  12. The EDA gene is a target of, but does not regulate Wnt signaling.
    Gene. 2002 Feb 20;285(1-2):203-11 PMID: 12039047
  13. Microarray analyses during adipogenesis: understanding the effects of Wnt signaling on adipogenesis and the roles of liver X receptor alpha in adipocyte metabolism.
    Mol Cell Biol. 2002 Aug;22(16):5989-99 PMID: 12138207
  14. A transcriptional response to Wnt protein in human embryonic carcinoma cells.
    BMC Dev Biol. 2002 Jul 2;2:8 PMID: 12095419
  15. Mechanisms of organogenetic tissue interaction.
    Natl Cancer Inst Monogr. 1967 Sep;26:279-99 PMID: 4864107
  16. Cloning of the T gene required in mesoderm formation in the mouse.
    Nature. 1990 Feb 15;343(6259):617-22 PMID: 2154694
  17. A thymus-specific member of the HMG protein family regulates the human T cell receptor C alpha enhancer.
    Genes Dev. 1991 Apr;5(4):656-69 PMID: 2010090
  18. LEF-1, a gene encoding a lymphoid-specific protein with an HMG domain, regulates T-cell receptor alpha enhancer function [corrected].
    Genes Dev. 1991 May;5(5):880-94 PMID: 1827423
  19. Identification of BMP-4 as a signal mediating secondary induction between epithelial and mesenchymal tissues during early tooth development.
    Cell. 1993 Oct 8;75(1):45-58 PMID: 8104708
  20. Mice homozygous for a targeted disruption of the proto-oncogene int-2 have developmental defects in the tail and inner ear.
    Development. 1993 Jan;117(1):13-28 PMID: 8223243
  21. Differential expression of the HMG box factors TCF-1 and LEF-1 during murine embryogenesis.
    Development. 1993 Jun;118(2):439-48 PMID: 8223271
  22. Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development.
    Nat Genet. 1994 Apr;6(4):348-56 PMID: 7914451
  23. Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in LEF-1-deficient mice.
    Genes Dev. 1994 Nov 15;8(22):2691-703 PMID: 7958926
  24. Interaction between a novel F9-specific factor and octamer-binding proteins is required for cell-type-restricted activity of the fibroblast growth factor 4 enhancer.
    Mol Cell Biol. 1994 Dec;14(12):7758-69 PMID: 7969117
  25. Requirement of FGF-4 for postimplantation mouse development.
    Science. 1995 Jan 13;267(5195):246-9 PMID: 7809630
  26. Lef1 expression is activated by BMP-4 and regulates inductive tissue interactions in tooth and hair development.
    Genes Dev. 1996 Jun 1;10(11):1382-94 PMID: 8647435
  27. Receptor specificity of the fibroblast growth factor family.
    J Biol Chem. 1996 Jun 21;271(25):15292-7 PMID: 8663044
  28. The mouse Engrailed-1 gene and ventral limb patterning.
    Nature. 1996 Jul 25;382(6589):360-3 PMID: 8684466
  29. The Shh signalling pathway in tooth development: defects in Gli2 and Gli3 mutants.
    Development. 1998 Aug;125(15):2803-11 PMID: 9655803
  30. Modulation of transcriptional regulation by LEF-1 in response to Wnt-1 signaling and association with beta-catenin.
    Mol Cell Biol. 1998 Aug;18(8):4807-18 PMID: 9671490
  31. Activin is an essential early mesenchymal signal in tooth development that is required for patterning of the murine dentition.
    Genes Dev. 1998 Aug 15;12(16):2636-49 PMID: 9716414
  32. Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities.
    Genes Dev. 1998 Sep 1;12(17):2735-47 PMID: 9732271
  33. Analysis of epithelial-mesenchymal interactions in the initial morphogenesis of the mammalian tooth.
    Dev Biol. 1998 Oct 15;202(2):215-27 PMID: 9769173
  34. De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin.
    Cell. 1998 Nov 25;95(5):605-14 PMID: 9845363
  35. Distinct regulatory elements govern Fgf4 gene expression in the mouse blastocyst, myotomes, and developing limb.
    Dev Biol. 1998 Dec 1;204(1):197-209 PMID: 9851853
  36. Morphogenesis.
    Cell. 1999 Jan 22;96(2):225-33 PMID: 9988217
  37. WNT targets. Repression and activation.
    Trends Genet. 1999 Jan;15(1):1-3 PMID: 10087922
  38. Wnt3a-/--like phenotype and limb deficiency in Lef1(-/-)Tcf1(-/-) mice.
    Genes Dev. 1999 Mar 15;13(6):709-17 PMID: 10090727
  39. Expression of Wnt signalling pathway genes during tooth development.
    Mech Dev. 1999 Jul;85(1-2):197-200 PMID: 10415363
  40. Antagonistic interactions between FGF and BMP signaling pathways: a mechanism for positioning the sites of tooth formation.
    Cell. 1997 Jul 25;90(2):247-55 PMID: 9244299
  41. Signalling networks regulating dental development.
    Mech Dev. 1997 Oct;67(2):111-23 PMID: 9392510
  42. Redundant regulation of T cell differentiation and TCRalpha gene expression by the transcription factors LEF-1 and TCF-1.
    Immunity. 1998 Jan;8(1):11-20 PMID: 9462507
  43. Soluble dominant-negative receptor uncovers essential roles for fibroblast growth factors in multi-organ induction and patterning.
    EMBO J. 1998 Mar 16;17(6):1642-55 PMID: 9501086
  44. Expression and function of FGFs-4, -8, and -9 suggest functional redundancy and repetitive use as epithelial signals during tooth morphogenesis.
    Dev Dyn. 1998 Mar;211(3):256-68 PMID: 9520113
  45. The roles of FGFs in the early development of vertebrate limbs.
    Genes Dev. 1998 Jun 1;12(11):1571-86 PMID: 9620845
  46. T (Brachyury) is a direct target of Wnt3a during paraxial mesoderm specification.
    Genes Dev. 1999 Dec 15;13(24):3185-90 PMID: 10617567
  47. An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal-epithelial signalling during mouse organogenesis.
    Development. 2000 Feb;127(3):483-92 PMID: 10631169
  48. Cusp patterning defect in Tabby mouse teeth and its partial rescue by FGF.
    Dev Biol. 1999 Dec 15;216(2):521-34 PMID: 10642790
  49. Normal limb development in conditional mutants of Fgf4.
    Development. 2000 Mar;127(5):989-96 PMID: 10662638
  50. Brachyury is a target gene of the Wnt/beta-catenin signaling pathway.
    Mech Dev. 2000 Mar 1;91(1-2):249-58 PMID: 10704849
  51. Reiterative signaling and patterning during mammalian tooth morphogenesis.
    Mech Dev. 2000 Mar 15;92(1):19-29 PMID: 10704885
  52. A new function of BMP4: dual role for BMP4 in regulation of Sonic hedgehog expression in the mouse tooth germ.
    Development. 2000 Apr;127(7):1431-43 PMID: 10704389
  53. Conditional inactivation of Fgf4 reveals complexity of signalling during limb bud development.
    Nat Genet. 2000 May;25(1):83-6 PMID: 10802662
  54. Edar/Eda interactions regulate enamel knot formation in tooth morphogenesis.
    Development. 2000 Nov;127(21):4691-700 PMID: 11023871
  55. BMP4 rescues a non-cell-autonomous function of Msx1 in tooth development.
    Development. 2000 Nov;127(21):4711-8 PMID: 11023873
  56. Sonic hedgehog regulates growth and morphogenesis of the tooth.
    Development. 2000 Nov;127(22):4775-85 PMID: 11044393
  57. FGF10 acts as a major ligand for FGF receptor 2 IIIb in mouse multi-organ development.
    Biochem Biophys Res Commun. 2000 Nov 2;277(3):643-9 PMID: 11062007
  58. Associations of FGF-3 and FGF-10 with signaling networks regulating tooth morphogenesis.
    Dev Dyn. 2000 Nov;219(3):322-32 PMID: 11066089
  59. Fibroblast growth factor receptor 2-IIIb acts upstream of Shh and Fgf4 and is required for limb bud maintenance but not for the induction of Fgf8, Fgf10, Msx1, or Bmp4.
    Dev Biol. 2001 Mar 1;231(1):47-62 PMID: 11180951
  60. Fibroblast growth factors.
    Genome Biol. 2001;2(3):REVIEWS3005 PMID: 11276432
  61. Male-to-female sex reversal in mice lacking fibroblast growth factor 9.
    Cell. 2001 Mar 23;104(6):875-89 PMID: 11290325
  62. WNT signals control FGF-dependent limb initiation and AER induction in the chick embryo.
    Cell. 2001 Mar 23;104(6):891-900 PMID: 11290326
  63. beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin.
    Cell. 2001 May 18;105(4):533-45 PMID: 11371349
  64. Rescue of a Wnt mutation by an activated form of LEF-1: regulation of maintenance but not initiation of Brachyury expression.
    Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8668-73 PMID: 11447280
  65. Lung hypoplasia and neonatal death in Fgf9-null mice identify this gene as an essential regulator of lung mesenchyme.
    Development. 2001 Jun;128(11):2095-106 PMID: 11493531
  66. FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak.
    Dev Cell. 2001 Jul;1(1):37-49 PMID: 11703922
  67. Expression of DeltaNLef1 in mouse epidermis results in differentiation of hair follicles into squamous epidermal cysts and formation of skin tumours.
    Development. 2002 Jan;129(1):95-109 PMID: 11782404
  68. The molars of the tabby mouse, and a test of the 'single-active X-chromosome' hypothesis.
    J Embryol Exp Morphol. 1966 Apr;15(2):223-44 PMID: 5959976
  69. Functional interaction of beta-catenin with the transcription factor LEF-1.
    Nature. 1996 Aug 15;382(6592):638-42 PMID: 8757136
  70. XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos.
    Cell. 1996 Aug 9;86(3):391-9 PMID: 8756721
Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.1035602
Published
2002-12-15
Pages
3173-85
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC187508
Subset
IM
External Links
PubMed source DOI: 10.1101/gad.1035602 PMC Full Text View journal details
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