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

Abstract

The Drosophila sprouty gene encodes an antagonist of FGF and EGF signaling whose expression is induced by the signaling pathways that it inhibits. Here we describe a family of vertebrate Sprouty homologs and demonstrate that the regulatory relationship with FGF pathways has been conserved. In both mouse and chick embryos, Sprouty genes are expressed in intimate association with FGF signaling centers. Gain- and loss-of-function experiments demonstrate that FGF signaling induces Sprouty gene expression in various tissues. Sprouty overexpression obtained by infecting the prospective wing territory of the chick embryo with a retrovirus containing a mouse Sprouty gene causes a reduction in limb bud outgrowth and other effects consistent with reduced FGF signaling from the apical ectodermal ridge. At later stages of development in the infected limbs there was a dramatic reduction in skeletal element length due to an inhibition of chondrocyte differentiation. The results provide evidence that vertebrate Sprouty proteins function as FGF-induced feedback inhibitors, and suggest a possible role for Sprouty genes in the pathogenesis of specific human chondrodysplasias caused by activating mutations in Fgfr3.

Sprouty3, but Not Sprouty1, Expression Is Beneficial for the Malignant Potential of Osteosarcoma Cells

“…Corroborating the ability to fulfill a tumor-promoting function in osteosarcoma, Spry3 proteins are heavily overexpressed in this bone tumor-derived cancer, while it is hardly detectable in normal human osteoblasts. This is in agreement with prior observations that Spry3 is primarily detected in brain and testis tissue [ 7 ]. Earlier, an increase of expression of this Spry form coinciding with the malignancy of the cancer cells was observed in brain associated tumors [ 30 ].…”

“…Earlier studies indicate that Spry3 expression in adult mammalians is restricted to the testis and brain [ 7 ]. To evaluate if Spry3 is expressed in cancer cells originating from different tissues, we first compared Spry3 expression in cell lines derived from lung, bone, colon and breast tumors with the levels observed in brain cancer-derived cell lines.…”

“…The presented data show that osteosarcoma-derived cells express prominent levels of the Spry3 protein. Earlier studies demonstrated that in contrast to Spry1, Spry2 and Spry4, which are ubiquitously expressed in all organs, Spry3 detection is limited to the brain and testis [ 7 ]. Subsequent reports verify an expression of Spry3 in cells of neuronal origin associated with a regulative function [ 38 ].…”

“…In mammals, four Spry homologues have been identified [ 7 ]. Knockout experiments in mice revealed that concomitant loss of Spry2 and Spry4 is lethal [ 8 ], while the lack of only Spry1 [ 9 , 10 ], Spry2 [ 11 , 12 ] or Spry4 [ 8 ] produces viable mice with specific phenotypes indicating that the functional compensation of the other Spry members is only partly.…”

Epigenetic DNA Modifications Upregulate SPRY2 in Human Colorectal Cancers

“…Sprouty (SPRY) mammalian proteins consist of 4 evolutionarily conserved family members (SPRY 1-4) that exhibit tissue-specific expression patterns, apart from the most conserved sprouty isoform SPRY2 that is ubiquitously expressed [1,2]. Sprouty proteins modulate cellular processes such as proliferation, motility, survival, and differentiation.…”