The role of Fgf10 signaling in branching morphogenesis and gene expression of the rat prostate gland:: lobe-specific suppression by neonatal estrogens
The role of Fgf10 signaling in branching morphogenesis and gene expression of the rat prostate gland:: lobe-specific suppression by neonatal estrogens
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DOI：
10.1016/j.ydbio.2004.11.020
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发表时间：
2005-02-15
影响因子：
2.7
通讯作者：
Prins, GS
中科院分区：
文献类型：
--
作者：
Huang, LW;Pu, YB;Prins, GS
大鼠在新生儿期短暂暴露于高剂量雌激素会以特定的方式中断前列腺的发育，并使腺体随着年龄的增长而发生发育不良，这种现象被称为发育性雌激素化。我们之前的研究表明，这些影响是通过改变类固醇受体表达开始的；然而，直接的下游目标仍不清楚。我们最近的研究表明，雌激素化后，Shh-ptc-gli的发育表达在前列腺背外侧下调，这在一定程度上导致了该前列腺区域的分支缺陷。在本研究中，我们研究了Fgf10信号在大鼠前列腺发育过程中的作用，并作为发育雌性化表型的中介。Fgf10和FgfR2iiib定位于不同前列腺叶的细长管和分支管的远端信号中心，在那里它们调节多种形态调节基因的表达，包括Shh、ptc、Bmp7、Bmp4、Hoyb13和Nkx3.1。腹侧叶器官培养和无间质导管培养表明Fgf10/Fg/R2iiib在导管伸长、分支、上皮增殖和分化中起直接作用。基于这些发现，我们提出了一个模型来描述前列腺发育中几个形态调节因子之间的局部表达和反馈回路，这些因子有助于严格调节的分支形态发生。与sh -ptc-gli类似，新生儿雌激素暴露下调前列腺背外侧Fgf10、FgfR2iiib和Bmp7的表达，而这些基因的腹侧叶表达不受影响。侧位前列腺器官培养实验表明，生长和分支抑制以及Fgf10/Fg/R2iiib抑制直接介导于前列腺水平。此外，外源性Fgf10完全挽救了雌激素暴露导致的生长和分支缺陷。总之，这些研究表明Fgf10信号的改变是Shh-ptc-gli和Bmp7下调的直接原因，它们共同导致新生儿雌激素暴露后前列腺背外侧分支抑制。(C) 2004爱思唯尔公司版权所有。
Brief exposure of rats to high-dose estrogen during the neonatal period interrupts prostate development in a lobe-specific manner and predisposes the gland to dysplasia with aging, a phenomenon referred to as developmental estrogenization. Our previous studies have revealed that these effects are initiated through altered steroid receptor expression; however, the immediate downstream targets remain unclear. We have recently shown that developmental expression of Shh-ptc-gli is downregulated in the dorsolateral prostate following estrogenization, and this is responsible, in part, for branching deficits observed in that prostatic region specifically. In the present study, we examine the role of Fgf10 signaling during rat prostate development and as a mediator of the developmental estrogenized phenotype. Fgf10 and FgfR2iiib localize to the distal signaling center of elongating and branching ducts in separate prostate lobes where they regulate the expression of multiple morphoregulatory genes including Shh, ptc, Bmp7, Bmp4, Hoyb13, and Nkx3.1. Ventral and lateral lobe organ cultures and mesenchyme-free ductal cultures demonstrate a direct role for Fgf10/Fg/R2iiib in ductal elongation, branching, epithelial proliferation, and differentiation. Based on these findings, a model is proposed depicting the localized expression and feedback loops between several morphoregulatory factors in the developing prostate that contribute to tightly regulated branching morphogenesis. Similar to Shh-ptc-gli, neonatal estrogen exposure downregulates Fgf10, FgfR2iiib, and Bmp7 expression in the dorsolateral prostate while ventral lobe expression of these genes is unaffected. Lateral prostate organ culture experiments demonstrate that growth and branching inhibition as well as Fgf10/Fg/R2iiib suppression are mediated directly at the prostatic level. Furthermore, exogenous Fgf10 fully rescues the growth and branching deficits due to estrogen exposure. Together, these studies demonstrate that alterations in Fgf10 signaling are a proximate cause of Shh-ptc-gli and Bmp7 downregulation that together result in branching inhibition of the dorsolateral prostate following neonatal estrogen exposure. (C) 2004 Elsevier Inc. All rights reserved.