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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.

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