Mukherjee Atish, Soyal Selma M, Fernandez-Valdivia Rodrigo, Gehin Martine, Chambon Pierre, Demayo Francesco J, Lydon John P, O'Malley Bert W
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Mol Cell Biol. 2006 Sep;26(17):6571-83. doi: 10.1128/MCB.00654-06.
Although the essential involvement of the progesterone receptor (PR) in female reproductive tissues is firmly established, the coregulators preferentially enlisted by PR to mediate its physiological effects have yet to be fully delineated. To further dissect the roles of members of the steroid receptor coactivator (SRC)/p160 family in PR-mediated reproductive processes in vivo, state-of-the-art cre-loxP engineering strategies were employed to generate a mouse model (PR(Cre/+) SRC-2(flox/flox)) in which SRC-2 function was abrogated only in cell lineages that express the PR. Fertility tests revealed that while ovarian activity was normal, PR(Cre/+) SRC-2(flox/flox) mouse uterine function was severely compromised. Absence of SRC-2 in PR-positive uterine cells was shown to contribute to an early block in embryo implantation, a phenotype not shared by SRC-1 or -3 knockout mice. In addition, histological and molecular analyses revealed an inability of the PR(Cre/+) SRC-2(flox/flox) mouse uterus to undergo the necessary cellular and molecular changes that precede complete P-induced decidual progression. Moreover, removal of SRC-1 in the PR(Cre/+) SRC-2(flox/flox) mouse uterus resulted in the absence of a decidual response, confirming that uterine SRC-2 and -1 cooperate in P-initiated transcriptional programs which lead to full decidualization. In the case of the mammary gland, whole-mount and histological analysis disclosed the absence of significant ductal side branching and alveologenesis in the hormone-treated PR(Cre/+) SRC-2(flox/flox) mammary gland, reinforcing an important role for SRC-2 in cellular proliferative changes that require PR. We conclude that SRC-2 is appropriated by PR in a subset of transcriptional cascades obligate for normal uterine and mammary morphogenesis and function.
尽管孕酮受体（PR）在女性生殖组织中的重要作用已得到确凿证实，但PR优先招募以介导其生理效应的共调节因子尚未完全明确。为了进一步剖析类固醇受体共激活因子（SRC）/p160家族成员在PR介导的体内生殖过程中的作用，采用了先进的cre-loxP基因工程策略构建了一种小鼠模型（PR(Cre/+) SRC-2(flox/flox)），其中SRC-2的功能仅在表达PR的细胞谱系中被消除。生育力测试表明，虽然卵巢活动正常，但PR(Cre/+) SRC-2(flox/flox)小鼠的子宫功能严重受损。PR阳性子宫细胞中缺乏SRC-2导致胚胎着床早期受阻，这一表型在SRC-1或-3基因敲除小鼠中并未出现。此外，组织学和分子分析显示，PR(Cre/+) SRC-2(flox/flox)小鼠子宫无法经历P诱导的完全蜕膜进展之前所需的细胞和分子变化。此外，在PR(Cre/+) SRC-2(flox/flox)小鼠子宫中去除SRC-1导致蜕膜反应缺失, 证实子宫SRC-2和-1在P启动的转录程序中协同作用，从而导致完全蜕膜化。在乳腺方面，整体和组织学分析显示，在激素处理的PR(Cre/+) SRC-2(flox/flox)乳腺中，没有明显的导管侧支分支和腺泡形成，这进一步证明了SRC-2在需要PR的细胞增殖变化中的重要作用。我们得出结论，在正常子宫和乳腺形态发生及功能所必需的一部分转录级联反应中，PR会募集SRC-2。
