Article

Coordinated activity of Spry1 and Spry2 is required for normal development of the external genitalia

Developmental Biology (Impact Factor: 3.64). 12/2013; 386(1). DOI: 10.1016/j.ydbio.2013.12.014
Source: PubMed

ABSTRACT 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.

1 Follower
 · 
65 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: One of the main functions of androgen is in the sexually dimorphic development of the male reproductive tissues. During embryogenesis, androgen determines the morphogenesis of male specific organs, such as the epididymis, seminal vesicle, prostate and penis. Despite the critical function of androgens in masculinization, the downstream molecular mechanisms of androgen signaling are poorly understood. Tissue recombination experiments and tissue specific androgen receptor (AR) knockout mouse studies have revealed epithelial or mesenchymal specific androgen-AR signaling functions. These findings also indicate that epithelial-mesenchymal interactions are a key feature of AR specific activity, and paracrine growth factor action may mediate some of the effects of androgens. This review focuses on mouse models showing the interactions of androgen and growth factor pathways that promote the sexual differentiation of reproductive organs. Recent studies investigating context dependent AR target genes are also discussed. This article is part of a Special Issue entitled: Nuclear receptors in animal development
    Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 01/2014; · 5.44 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Sprouty proteins are evolutionarily conserved modulators of MAPK/ERK pathway. Through interacting with an increasing number of effectors, mediators, and regulators with ultimate influence on multiple targets within or beyond ERK, Sprouty orchestrates a complex, multilayered regulatory system and mediates a crosstalk among different signaling pathways for a coordinated cellular response. As such, Sprouty has been implicated in various developmental and physiological processes. Evidence shows that ERK is aberrantly activated in malignant conditions. Accordingly, Sprouty deregulation has been reported in different cancer types and shown to impact cancer development, progression, and metastasis. In this article, we have tried to provide an overview of the current knowledge about the Sprouty physiology and its regulatory functions in health, as well as an updated review of the Sprouty status in cancer. Putative implications of Sprouty in cancer biology, their clinical relevance, and their proposed applications are also revisited. As a developing story, however, role of Sprouty in cancer remains to be further elucidated.
    CANCER AND METASTASIS REVIEW 04/2014; 33(2-3). DOI:10.1007/s10555-014-9497-1 · 7.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: One of the main functions of androgen is in the sexually dimorphic development of the male reproductive tissues. During embryogenesis, androgen determines the morphogenesis of male specific organs, such as the epididymis, seminal vesicle, prostate and penis. Despite the critical function of androgens in masculinization, the downstream molecular mechanisms of androgen signaling are poorly understood. Tissue recombination experiments and tissue specific androgen receptor (AR) knockout mouse studies have revealed epithelial or mesenchymal specific androgen-AR signaling functions. These findings also indicate that epithelial-mesenchymal interactions are a key feature of AR specific activity, and paracrine growth factor action may mediate some of the effects of androgens. This review focuses on mouse models showing the interactions of androgen and growth factor pathways that promote the sexual differentiation of reproductive organs. Recent studies investigating context dependent AR target genes are also discussed. This article is part of a Special Issue entitled: Nuclear receptors in animal development.
    Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 05/2014; 1849(2). DOI:10.1016/j.bbagrm.2014.05.020 · 5.44 Impact Factor
Show more