Coordinated activity of Spry1 and Spry2 is required for normal development of the external genitalia.
Coordinated activity of Spry1 and Spry2 is required for normal development of the external genitalia.
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DOI：
10.1016/j.ydbio.2013.12.014
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发表时间：
2014-02-01
影响因子：
2.7
通讯作者：
Klein, Ophir D.
中科院分区：
文献类型：
--
作者：
Ching, Saunders T.;Cunha, Gerald R.;Baskin, Laurence S.;Basson, M. Albert;Klein, Ophir D.
哺乳动物外生殖器的发育受信号分子和转录因子网络控制。由于FGF信号在这一复杂的形态发生过程中起着核心作用，我们研究了Sprouty基因在小鼠外生殖器胚胎发育过程中的作用，Sprouty基因是FGF信号的重要细胞内调节剂。我们发现Sprouty基因在胚胎发育过程中由尿道上皮表达，并且它们在尿道形成和融合过程中具有关键功能。生殖器结节（GT），原基的包皮和男性阴茎头和阴蒂头的女性，严重影响男性胚胎携带空等位基因的Spry 1和Spry 2。在Spry 1 −/−; Spry 2 −/−胚胎中，内管状尿道缺失，尿路上皮形态和组织异常。这些影响部分是由于Spry 1 −/−; Spry 2 −/−胚胎中上皮细胞增殖水平升高。尽管整体组织的变化，终末分化的尿路上皮没有显着影响。对调节正常GT发育的分子途径的表征证实，Sprouty基因的缺失导致FGF信号传导升高，而其他级联中的信号传导水平在很大程度上得以保留。总之，这些结果表明，FGF信号传导的水平必须在小鼠外生殖器的胚胎发育过程中受到严格调控，并且这种调控部分是通过Sprouty基因产物的活性介导的。
Development of the mammalian external genitalia is controlled by a network of signaling molecules and transcription factors. Because FGF signaling plays a central role in this complicated morphogenetic process, we investigated the role of Sprouty genes, which are important intracellular modulators of FGF signaling, during embryonic development of the external genitalia in mice. We found that Sprouty genes are expressed by the urethral epithelium during embryogenesis, and that they have a critical function during urethral canalization and fusion. Development of the genital tubercle (GT), the anlage to the prepuce and glans penis in males and glans clitoris in females, was severely affected in male embryos carrying null alleles of both Spry1 and Spry2. In Spry1−/−;Spry2−/− embryos, the internal tubular urethra was absent, and urothelial morphology and organization was abnormal. These effects were due, in part, to elevated levels of epithelial cell proliferation in Spry1−/−;Spry2−/− embryos. Despite changes in overall organization, terminal differentiation of the urothelium was not significantly affected. Characterization of the molecular pathways that regulate normal GT development confirmed that deletion of Sprouty genes leads to elevated FGF signaling, whereas levels of signaling in other cascades were largely preserved. Together, these results show that levels of FGF signaling must be tightly regulated during embryonic development of the external genitalia in mice, and that this regulation is mediated in part through the activity of Sprouty gene products.
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