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FGFR3 is a target of the homeobox transcription factor SHOX in limb development.

Abstract
The short stature homeobox gene SHOX encodes a transcription factor which is important for normal limb development. In humans, SHOX deficiency has been associated with various short stature syndromes including Leri-Weill dyschondrosteosis (LWD), Langer mesomelic dysplasia and Turner syndrome as well as non-syndromic idiopathic short stature. A common feature of these syndromes is disproportionate short stature with a particular shortening of the forearms and lower legs. In our studies employing microarray analyses and cell culture experiments, we revealed a strong positive effect of SHOX on the expression of the fibroblast growth factor receptor gene FGFR3, another well-known factor for limb development. Luciferase reporter gene assays show that SHOX activates the extended FGFR3 promoter, and results from chromatin immunoprecipitation (ChIP)-sequencing, ChIP and electrophoretic mobility shift assay experiments suggest a direct binding of SHOX to multiple upstream sequences of FGFR3. To further investigate these regulations in a cellular system for limb development, the effect of viral overexpression of Shox in limb bud derived chicken micromass cultures was tested. We found that Fgfr3 was negatively regulated by Shox, as demonstrated by quantitative real-time polymerase chain reaction and in situ hybridization. This repressive effect might explain the almost mutually exclusive expression patterns of Fgfr3 and Shox in embryonic chicken limbs. A negative regulation that occurs mainly in the mesomelic segments, a region where SHOX is known to be strongly expressed, offers a possible explanation for the phenotypes seen in patients with FGFR3 (e.g. achondroplasia) and SHOX defects (e.g. LWD). In summary, these data present a link between two frequent short stature phenotypes.
AuthorsEva Decker, Claudia Durand, Sebastian Bender, Christian Rödelsperger, Anne Glaser, Jochen Hecht, Katja U Schneider, Gudrun Rappold
JournalHuman molecular genetics (Hum Mol Genet) Vol. 20 Issue 8 Pg. 1524-35 (Apr 15 2011) ISSN: 1460-2083 [Electronic] England
PMID21273290 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Homeodomain Proteins
  • Recombinant Proteins
  • SHOX protein, human
  • Short Stature Homeobox Protein
  • Luciferases, Firefly
  • Receptor, Fibroblast Growth Factor, Type 3
Topics
  • Animals
  • Base Sequence
  • Cell Line, Tumor
  • Chick Embryo
  • Chondrocytes (metabolism)
  • Down-Regulation
  • Ectoderm (metabolism)
  • Genes, Reporter
  • Hindlimb (cytology, embryology, metabolism)
  • Homeodomain Proteins (genetics, metabolism)
  • Humans
  • Luciferases, Firefly (biosynthesis, genetics)
  • Mesoderm (metabolism)
  • Molecular Sequence Data
  • Mutation, Missense
  • Phenotype
  • Promoter Regions, Genetic
  • RNA Interference
  • Receptor, Fibroblast Growth Factor, Type 3 (genetics, metabolism)
  • Recombinant Proteins (genetics, metabolism)
  • Short Stature Homeobox Protein
  • Transcription, Genetic
  • Wings, Animal (cytology, embryology, metabolism)

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