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.
de Frutos
Cristina A
CA
Instituto de Neurociencias de Alicante, CSIC-UMH, Apartado 18, San Juan de Alicante 03550, Spain.
Vega
Sonia
S
Manzanares
Miguel
M
Flores
Juana M
JM
Huertas
Hector
H
Martínez-Frías
M Luisa
ML
Nieto
M Angela
MA
D000130:Achondroplasia / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002356:Cartilage / Q000378:metabolism; D049109:Cell Proliferation; D019902:Chondrocytes / Q000378:metabolism*; D020219:Chondrogenesis / Q000502:physiology*; D006614:Hindlimb / Q000196:embryology / Q000378:metabolism; D006801:Humans; D051379:Mice / Q000196:embryology; D008822:Mice, Transgenic; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic
C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D013629:Tamoxifen; D051498:Receptor, Fibroblast Growth Factor, Type 3