Lipinski Robert J, Cook Crist H, Barnett Daniel H, Gipp Jerry J, Peterson Richard E, Bushman Wade
Division of Urology, Department of Surgery, University of Wisconsin-Madison, Madison, Wisconsin 53792, USA.
Dev Dyn. 2005 Jul;233(3):829-36. doi: 10.1002/dvdy.20414.
At the onset of ductal morphogenesis in the developing prostate, Shh expression condenses at evaginations of urogenital sinus epithelium and activates Gli transcription factors in the adjacent mesenchyme. Abrogation of Hedgehog signaling disrupts proper prostatic budding, ductal growth, and branching. We now show that Hedgehog signaling regulates the expression of insulin-like growth factor binding protein-6 (Igfbp-6) in the developing mouse prostate. Igfbp-6 is a secreted factor that specifically binds insulin-like growth factor-II (IGF-II), prevents its binding to the IGF-I receptor, and is thought to regulate the activity of IGF-II in growth and differentiation. Igfbp-6 is expressed in both the developing and adult prostate. In the urogenital sinus, Igfbp-6 mRNA colocalized with Ptc1 and Gli1 mRNA in the mesenchyme, while Igfbp-6 protein was found in both the mesenchymal and epithelial layers. Exogenous Shh peptide induced expression of Igfbp-6 in the developing prostate while the chemical inhibitor of Hedgehog signaling, cyclopamine, reduced its expression. These studies show that Igfbp-6 is an actual target of Shh signaling in the urogenital sinus and provide the first evidence for a linkage between the Hedgehog and IGF signaling pathways in prostate development.
在发育中的前列腺导管形态发生开始时， Sonic Hedgehog （Shh）表达在泌尿生殖窦上皮的内陷处聚集，并激活相邻间充质中的Gli转录因子。Hedgehog信号的消除会破坏前列腺的正常出芽、导管生长和分支。我们现在表明，Hedgehog信号调节发育中小鼠前列腺中胰岛素样生长因子结合蛋白-6（Igfbp-6）的表达。Igfbp-6是一种分泌因子，它特异性结合胰岛素样生长因子-II（IGF-II），阻止其与IGF-I受体结合，并被认为在生长和分化中调节IGF-II的活性。Igfbp-6在发育中的前列腺和成年前列腺中均有表达。在泌尿生殖窦中，Igfbp-6 mRNA与间充质中的Ptc1和Gli1 mRNA共定位，而Igfbp-6蛋白则在间充质层和上皮层中均有发现。外源性Shh肽诱导发育中的前列腺中Igfbp-6的表达，而Hedgehog信号的化学抑制剂环杷明则降低其表达。这些研究表明，Igfbp-6是泌尿生殖窦中Shh信号的实际靶点，并为前列腺发育中Hedgehog和IGF信号通路之间的联系提供了首个证据。
