Vertebrate Sprouty genes are induced by FGF signaling and can cause chondrodysplasia when overexpressed

The Drosophila sprouty gene encodes an antagonist of FGF and EGF signaling whose expression is induced by the signaling pathways that it inhibits. Her e we describe a family of vertebrate Sprouty homologs and demonstrate that the regulatory relationship with FGF pathways has been conserved. In both m ouse and chick embryos, Sprouty genes are expressed in intimate association with FGF signaling centers, Gain- and loss-of-function experiments demonst rate that FGF signaling induces Sprouty gene expression in various tissues, Sprouty overexpression obtained by infecting the prospective wing territor y of the chick embryo with a retrovirus containing a mouse Sprouty gene cau ses a reduction in limb bud outgrowth and other effects consistent with red uced FGF signaling from the apical ectodermal ridge. At later stages of dev elopment in the infected limbs there was a dramatic reduction in skeletal e lement length due to an inhibition of chondrocyte differentiation. The resu lts provide evidence that vertebrate Sprouty proteins function as FGF-induc ed feedback inhibitors, and suggest a possible role for Sprouty genes in th e pathogenesis of specific human chondrodysplasias caused by activating mut ations in Fgfr3.