Minowada G, Jarvis L A, Chi C L, Neubüser A, Sun X, Hacohen N, Krasnow M A, Martin G R
Department of Anatomy and Program in Developmental Biology, School of Medicine, University of California, San Francisco, CA 94143-0452, USA.
Development. 1999 Oct;126(20):4465-75. doi: 10.1242/dev.126.20.4465.
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.
果蝇的spry基因编码一种FGF和EGF信号通路的拮抗剂，其表达由它所抑制的信号通路诱导产生。在此，我们描述了一个脊椎动物Spry同源物家族，并证明其与FGF信号通路的调控关系是保守的。在小鼠和鸡胚胎中，Spry基因都与FGF信号中心紧密相关地表达。功能获得和功能丧失实验表明，FGF信号在各种组织中诱导Spry基因表达。通过用含有小鼠Spry基因的逆转录病毒感染鸡胚胎的预期翅区获得的Spry过表达，导致肢芽生长减少以及与来自顶端外胚层嵴的FGF信号减少一致的其他效应。在感染肢体发育的后期，由于软骨细胞分化受到抑制，骨骼元素长度显著缩短。这些结果提供了证据，表明脊椎动物Spry蛋白作为FGF诱导的反馈抑制剂发挥作用，并提示Spry基因在由Fgfr3激活突变引起的特定人类软骨发育不全的发病机制中可能发挥作用。
