Fibroblast growth factor receptor signaling through MEK-ERK is required for prostate bud induction
Fibroblast growth factor receptor signaling through MEK-ERK is required for prostate bud induction
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DOI：
10.1111/j.1432-0436.2006.00161.x
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发表时间：
2007-09-01
期刊：
影响因子：
2.9
通讯作者：
Marker, Paul C.
中科院分区：
文献类型：
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作者：
Kuslak, Sheri L.;Marker, Paul C.
在小鼠胚胎约15.5天左右，泌尿生殖窦（UGS）被确定为前列腺，这由转录因子Nkx3.1的表达所表明。此后不久，上皮芽向泌尿生殖窦间充质生长启动前列腺形态发生。对体内雄性和雌性泌尿生殖窦的比较表明，在与上皮芽形成同时发生的分支形态发生调控基因存在性别二态性表达，包括Bmp7、Gli1、Gli2、Fgf10、Ptch1和Shh。在无血清器官培养中，对有或无睾酮条件下生长的泌尿生殖窦进行比较，结果显示在前列腺芽诱导过程中观察到的一些但并非所有性别二态性差异在体外都能有效模拟。然后利用器官培养来研究成纤维细胞生长因子受体（FGFR）信号在前列腺诱导过程中的作用。用PD173074阻断FGFR激活表明，泌尿生殖窦中细胞外信号调节激酶1/2（ERK1/2）的激活依赖于FGFR信号。此外，用PD173074抑制FGFR激活或用UO126抑制ERK1/2激活，可阻断雄激素在泌尿生殖窦中诱导的所有形态发生、增殖和基因表达变化。这些数据揭示了ERK1/2在前列腺芽诱导过程中一个先前未知的作用。它们还表明，FGFR通过ERK1/2的信号传导对于雄激素诱导的前列腺芽诱导过程中的芽形态发生、增殖和基因表达是必需的。
The urogenital sinus (UGS) is specified as prostate in mice around embryonic day 15.5 as indicated by expression of the transcription factor Nkx3.1. Shortly thereafter, growth of epithelial buds into the UGS mesenchyme initiates prostatic morphogenesis. A comparison of male and female UGSs in vivo demonstrated sexually dimorphic expression of branching morphogenesis regulatory genes coincident with epithelial budding including Bmp7, Gli1, Gli2, Fgf10, Ptch1, and Shh. A comparison of UGSs grown with or without testosterone in serum-free organ cultures showed that some, but not all sexually dimorphic differences observed during prostate bud induction, were effectively modeled in vitro. Organ cultures were then used to investigate the role of fibroblast growth factor receptor (FGFR) signaling during prostatic induction. Blocking FGFR activation with PD173074 showed that activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the UGS is dependent on FGFR signaling. Furthermore, inhibiting either FGFR activation with PD173074 or ERK1/2 activation with UO126 blocked all morphogenesis, proliferation, and gene expression changes induced by androgens in the UGS. These data reveal a previously unknown role for ERK1/2 during prostate bud induction. They also show that signaling by FGFRs through ERK1/2 is required for androgen-induced budding morphogenesis, proliferation, and gene expression during prostate bud induction.