FKBP52 deficiency-conferred uterine progesterone resistance is genetic background and pregnancy stage specific
FKBP52 deficiency-conferred uterine progesterone resistance is genetic background and pregnancy stage specific
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DOI：
10.1172/jci31622
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发表时间：
2007-07-01
影响因子：
15.9
通讯作者：
Dey, Sudhansu K.
中科院分区：
文献类型：
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作者：
Tranguch, Susanne;Wang, Haibin;Dey, Sudhansu K.
亲免疫素FKBP 52作为辅伴侣来控制正常的孕酮（P-4）受体（PR）功能。使用Fkbp 52（-/-）小鼠，我们显示了妊娠期间子宫P-4/PR信号传导的有趣方面。着床失败是在这些无效雌性中发现的主要表型，其在C57 BL 6/129和CD 1背景中均是保守的。然而，P-4补充拯救植入和随后的蜕膜化在CD 1，但不是C57 BL 6/129，空的女性。令人惊讶的是，在不存在胚泡的情况下，实验诱导的蜕膜化在Fkbp 52（-/-）小鼠中在任一背景下失败，即使补充P-4，这表明胚胎信号补充了该事件的子宫信号传导。另一个有趣的发现是，虽然P-4在高于正常妊娠水平赋予PR信号足以植入在CD 1无效的女性，这些水平是无效的，在维持妊娠到足月。然而，升高P-4水平进一步恢复PR信号传导至具有正常产仔数的成功足月妊娠的最佳水平。总的来说，结果表明FKBP 52在子宫P-4/PR信号传导中的不可或缺性是遗传差异的函数，并且是妊娠阶段特异性的。由于有证据表明P4补充剂与P-4抵抗性复发性流产和子宫内膜异位症缓解的风险降低之间存在相关性，因此这些发现对遗传多样性的女性人群具有临床意义。
Immunophilin FKBP52 serves as a cochaperone to govern normal progesterone (P-4) receptor (PR) function. Using Fkbp52(-/-) mice, we show intriguing aspects of uterine P-4/PR signaling during pregnancy. Implantation failure is the major phenotype found in these null females, which is conserved on both C57BL6/129 and CD1 backgrounds. However, P-4 supplementation rescued implantation and subsequent decidualization in CD1, but not C57BL6/129, null females. Surprisingly, experimentally induced decidualization in the absence of blastocysts failed in Fkbp52(-/-) mice on either background even with P-4 supplementation, suggesting that embryonic signals complement uterine signaling for this event. Another interesting finding was that while P-4 at higher than normal pregnancy levels conferred PR signaling sufficient for implantation in CD1 null females, these levels were inefficient in maintaining pregnancy to full term. However, elevating P-4 levels further restored PR signaling to a level optimal for successful term pregnancy with normal litter size. Collectively, the results show that the indispensability of FKBP52 in uterine P-4/PR signaling is a function of genetic disparity and is pregnancy stage specific. Since there is evidence for a correlation between P4 supplementation and reduced risks of P-4-resistant recurrent miscarriages and remission of endometriosis, these findings have clinical implications for genetically diverse populations of women.