Reduced prostate branching morphogenesis in stromal fibroblast, but not in epithelial, estrogen receptor α knockout mice
Reduced prostate branching morphogenesis in stromal fibroblast, but not in epithelial, estrogen receptor α knockout mice
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DOI：
10.1038/aja.2011.181
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发表时间：
2012-07-01
影响因子：
2.9
通讯作者：
Yeh, Shuyuan
中科院分区：
文献类型：
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作者：
Chen, Ming;Yeh, Chiuan-Ren;Yeh, Shuyuan
早期研究表明，雌激素受体α(ERα)参与了雌激素在前列腺发育中的印迹效应。我们最近报道了一种更完整的ERα基因敲除(KO)小鼠模型，方法是将β-肌动蛋白Cre转基因小鼠与ERα小鼠配对。这些ACTB-ERαKO雄性小鼠在前列腺分支形态发生方面存在缺陷，这表明ERα是维持前列腺增殖事件所必需的。然而，哪种前列腺型ERα在其中发挥这些重要功能仍有待阐明。为了解决这个问题，我们用成纤维细胞特异性蛋白(FSP)-Cre或原盆-Cre转基因小鼠培育ERα小鼠，以产生一种在间质成纤维细胞(FSP-ERαKO)或上皮细胞(PES-ERαKO)中缺失ERα基因的小鼠模型。我们发现FSP-ERαKO和PES-ERαKO雄性小鼠的循环睾酮和生育力没有改变。与野生型相比，FSP-ERαKO小鼠的前列腺具有较少的分枝形态发生。进一步分析表明，内质网α的缺失导致间质细胞凋亡增加，胰岛素样生长因子-1(IGF-1)和FGF10的表达减少，BMP4的表达增加。总之，我们已经建立了第一个体内前列腺间质和上皮选择性ERαKO小鼠模型，这些小鼠的结果表明，间质成纤维细胞ERα通过旁分泌方式在前列腺分支形态发生中发挥重要作用。PROPOWER-CRE选择性缺失小鼠前列腺上皮细胞ERα基因不影响正常的前列腺发育和内环境稳定。《亚洲男科学杂志》(2012年)14546-555；DOI：10.1038/aja.2011.181；2012年5月21日在线出版
Early studies suggested that estrogen receptor alpha (ER alpha) is involved in estrogen-mediated imprinting effects in prostate development. We recently reported a more complete ER alpha knockout (KO) mouse model via mating beta-actin Cre transgenic mice with floxed ER alpha mice. These ACTB-ER alpha KO male mice showed defects in prostatic branching morphogenesis, which demonstrates that ER alpha is necessary to maintain proliferative events in the prostate. However, within which prostate cell type ER alpha exerts those important functions remains to be elucidated. To address this, we have bred floxed ER alpha mice with either fibroblast-specific protein (FSP)-Cre or probasin-Cre transgenic mice to generate a mouse model that has deleted ER alpha gene in either stromal fibroblast (FSP-ER alpha KO) or epithelial (pes-ER alpha KO) prostate cells. We found that circulating testosterone and fertility were not altered in FSP-ER alpha KO and pes-ER alpha KO male mice. Prostates of FSP-ER alpha KO mice have less branching morphogenesis compared to that of wild-type littermates. Further analyses indicated that loss of stromal ER alpha leads to increased stromal apoptosis, reduced expression of insulin-like growth factor-1 (IGF-1) and FGF10, and increased expression of BMP4. Collectively, we have established the first in vivo prostate stromal and epithelial selective ER alpha KOmouse models and the results from these mice indicated that stromal fibroblast ER alpha plays important roles in prostatic branching morphogenesis via a paracrine fashion. Selective deletion of the ER alpha gene in mouse prostate epithelial cells by probasin-Cre does not affect the regular prostate development and homeostasis. Asian Journal of Andrology (2012) 14, 546-555; doi:10.1038/aja.2011.181; published online 21 May 2012