Snail1 is a transcriptional effector of FGFR3 signaling during chondrogenesis and achondroplasias.

Achondroplasias are the most common genetic forms of dwarfism in humans. They are associated with activating mutations in FGFR3, which signal through the Stat and MAPK pathways in a ligand-independent manner to impair chondrocyte proliferation and differentiation. Snail1 has been implicated in chondrocyte differentiation as it represses Collagen II and aggrecan transcription in vitro. Here we demonstrate that Snail1 overexpression in the developing bone leads to achondroplasia in mice. Snail1 acts downstream of FGFR3 signaling in chondrocytes, regulating both Stat and MAPK pathways. Moreover, FGFR3 requires Snail1 during bone development and disease as the inhibition of Snail1 abolishes its signaling even through achondroplastic- and thanatophoric-activating FGFR3 forms. Significantly, Snail1 is aberrantly upregulated in thanatophoric versus normal cartilages from stillborns. Thus, Snail activity may likely be considered a target for achondroplasia therapies.

[1]  D. Church,et al.  Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia , 1994, Cell.

[2]  Francisco Portillo,et al.  The transcription factor Snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression , 2000, Nature Cell Biology.

[3]  P. Prinos,et al.  A common FGFR3 gene mutation in hypochondroplasia. , 1995, Human molecular genetics.

[4]  C. Deng,et al.  Mouse Models Orthologous to FGFR3-Related Skeletal Dysplasias , 2003, Pediatric pathology & molecular medicine.

[5]  S. Murakami,et al.  Constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype. , 2004, Genes & development.

[6]  C. Deng,et al.  A neonatal lethal mutation in FGFR3 uncouples proliferation and differentiation of growth plate chondrocytes in embryos. , 2000, Human molecular genetics.

[7]  F. Beier,et al.  RhoA/ROCK Signaling Regulates Chondrogenesis in a Context-dependent Manner* , 2006, Journal of Biological Chemistry.

[8]  Xin-Yuan Fu,et al.  Activation of Statl by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism , 1997, Nature.

[9]  E. Wagner,et al.  Reaching a genetic and molecular understanding of skeletal development. , 2002, Developmental cell.

[10]  D. Givol,et al.  A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[11]  F. Mallein-Gerin,et al.  Different effects of bone morphogenetic proteins 2, 4, 12, and 13 on the expression of cartilage and bone markers in the MC615 chondrocyte cell line. , 1999, Experimental cell research.

[12]  C. Deng,et al.  A Lys644Glu substitution in fibroblast growth factor receptor 3 (FGFR3) causes dwarfism in mice by activation of STATs and ink4 cell cycle inhibitors. , 1999, Human molecular genetics.

[13]  A. Yayon,et al.  Fibroblast growth factor receptor-3 as a therapeutic target for Achondroplasia--genetic short limbed dwarfism. , 2003, Current drug targets.

[14]  C. Deng,et al.  Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis. , 1999, The Journal of clinical investigation.

[15]  I. Fabregat,et al.  Snail blocks the cell cycle and confers resistance to cell death. , 2004, Genes & development.

[16]  B. Hogan,et al.  Manipulating the mouse embryo: A laboratory manual , 1986 .

[17]  D. Ornitz,et al.  Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia , 1996, Nature Genetics.

[18]  D. Riethmacher,et al.  A targeted mutation in the mouse E-cadherin gene results in defective preimplantation development. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Quintanilla,et al.  Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions. , 2003, The Journal of biological chemistry.

[20]  T. Underhill,et al.  p38 MAP kinase signalling is required for hypertrophic chondrocyte differentiation. , 2004, The Biochemical journal.

[21]  Gary W. Harding,et al.  Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3 , 1996, Nature Genetics.

[22]  S. Murakami,et al.  Up-regulation of the chondrogenic Sox9 gene by fibroblast growth factors is mediated by the mitogen-activated protein kinase pathway. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Y. Nabeshima,et al.  Mouse Snail Family Transcription Repressors Regulate Chondrocyte, Extracellular Matrix, Type II Collagen, and Aggrecan* , 2003, Journal of Biological Chemistry.

[24]  G. Segre,et al.  Expression of parathyroid hormone-related peptide and its receptor messenger ribonucleic acids during fetal development of rats. , 1995, Endocrinology.

[25]  M. Nieto,et al.  The snail superfamily of zinc-finger transcription factors , 2002, Nature Reviews Molecular Cell Biology.

[26]  Q. Wang,et al.  Differential regulation of endochondral bone growth and joint development by FGFR1 and FGFR3 tyrosine kinase domains. , 2001, Development.

[27]  K. Nakao,et al.  Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway , 2004, Nature Medicine.

[28]  S. Murakami,et al.  Constitutive activation of MKK6 in chondrocytes of transgenic mice inhibits proliferation and delays endochondral bone formation. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[29]  M. Nieto,et al.  The Snail genes as inducers of cell movement and survival: implications in development and cancer , 2005, Development.

[30]  M. Nieto,et al.  Snail activation disrupts tissue homeostasis and induces fibrosis in the adult kidney , 2006, The EMBO journal.

[31]  I. Kaitila,et al.  Achondroplasia is defined by recurrent G380R mutations of FGFR3. , 1995, American journal of human genetics.

[32]  W. Horton.  Recent milestones in achondroplasia research , 2006, American journal of medical genetics. Part A.

[33]  D. Rimoin,et al.  Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3 , 1995, Nature Genetics.

[34]  D. Rimoin,et al.  Another mutation that results in the substitution of an unpaired cysteine residue in the extracellular domain of FGFR3 in thanatophoric dysplasia type I. , 1995, Human molecular genetics.

[35]  A. Munnich,et al.  Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1). , 1996, Human molecular genetics.

[36]  Andrew P McMahon,et al.  Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. , 2002, Developmental biology.

[37]  Arnold Munnich,et al.  Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia , 1994, Nature.

[38]  W. Horton,et al.  Fibroblast growth factor receptor 3 and the human chondrodysplasias. , 1997, Current opinion in pediatrics.

[39]  A. Munnich,et al.  Overexpression of FGFR3, Stat1, Stat5 and p21Cip1 correlates with phenotypic severity and defective chondrocyte differentiation in FGFR3-related chondrodysplasias. , 2004, Bone.

[40]  P. Leder,et al.  Fibroblast Growth Factor Receptor 3 Is a Negative Regulator of Bone Growth , 1996, Cell.

[41]  P Chambon,et al.  Ligand-activated site-specific recombination in mice. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[42]  D. Levy,et al.  FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway. , 1999, Genes & development.

[43]  M. Knowles,et al.  Cell responses to FGFR3 signalling: growth, differentiation and apoptosis. , 2005, Experimental cell research.

[44]  I. Kaitila,et al.  A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia , 1995, Nature Genetics.

[45]  M. Bennett,et al.  Cloning and developmental expression of Sna, a murine homologue of the Drosophila snail gene. , 1992, Development.

[46]  E. Laplantine,et al.  A network of transcriptional and signaling events is activated by FGF to induce chondrocyte growth arrest and differentiation , 2003, The Journal of cell biology.

[47]  D. Ornitz,et al.  Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. , 1998, Development.

[48]  A. Munnich,et al.  Stop codon FGFR3 mutations in thanatophoric dwarfism type 1 , 1995, Nature Genetics.

[49]  H. Kronenberg,et al.  Developmental regulation of the growth plate , 2003, Nature.

[50]  P. Marie,et al.  FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. , 2002, Genes & development.

[51]  S. Dimitrov,et al.  Phosphorylation of serine 10 in histone H3, what for? , 2003, Journal of Cell Science.

[52]  E. Laplantine,et al.  Activation of the ERK1/2 and p38 Mitogen-activated Protein Kinase Pathways Mediates Fibroblast Growth Factor-induced Growth Arrest of Chondrocytes* , 2004, Journal of Biological Chemistry.

[53]  Ellen M. Leiferman,et al.  Differential growth by growth plates as a function of multiple parameters of chondrocytic kinetics , 1996, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.