The epidermal growth factor receptor critically regulates endometrial function during early pregnancy.
The epidermal growth factor receptor critically regulates endometrial function during early pregnancy.
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DOI：
10.1371/journal.pgen.1004451
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发表时间：
2014-06
期刊：
影响因子：
4.5
通讯作者：
DeMayo FJ
中科院分区：
文献类型：
--
作者：
Large MJ;Wetendorf M;Lanz RB;Hartig SM;Creighton CJ;Mancini MA;Kovanci E;Lee KF;Threadgill DW;Lydon JP;Jeong JW;DeMayo FJ
不孕症和不良妇科结局，如先兆子痫和流产，代表了重要的女性生殖健康问题。生长因子的时空表达表明它们在妊娠中起重要作用。本研究的目的是明确ERBB家族生长因子受体在子宫内膜功能中的作用。使用小鼠条件消融和siRNA在原代人子宫内膜间质细胞，我们确定了表皮生长因子受体（Egfr）是子宫内膜功能在妊娠早期的关键。虽然Her 2或Erbb 3的消融仅导致窝仔数的适度减少，但缺乏Egfr表达的小鼠严重生育力低下。由于蜕膜化缺陷，包括增殖、细胞存活、分化和靶基因表达降低，在胚泡植入后不久发生妊娠死亡。为了将Egfr置于遗传调控层级中，转录组分析用于比较来自具有Egfr、无翅相关MMTV整合位点4（Wnt 4）或无骨形态发生蛋白2（Bmp 2）的条件性消融的小鼠的基因特征;揭示Bmp 2和Wnt 4不仅是Egfr的关键下游效应子，而且它们还调节不同的生理功能。在原代人子宫内膜间质细胞中，标记基因表达，一种新的高含量的基于图像的方法和磷酸激酶阵列分析被用来证明EGFR是人蜕膜化的关键调节因子。此外，抑制EGFR信号传导中间体WNK 1和AKT 1 S1，在激酶阵列中鉴定的成员和以前未报道的在子宫内膜中发挥作用，也减弱蜕膜化。这些结果表明，EGFR通过激活复杂的信号传导和转录网络，在建立成功妊娠所需的细胞环境中发挥着不可或缺的作用，从而为潜在的治疗靶点提供了有价值的见解。大约10%的育龄妇女被认为是不育的。虽然在辅助生殖技术方面取得了长足进步，但总体成功率，特别是考虑到成本，仍然很低。研究表明，由于其连续性，近75%的妊娠失败是由于妊娠早期发生的缺陷。因此，如果我们要提高解决女性生殖健康问题的能力，了解这一时期子宫内膜发生的生理变化以及这些变化是如何调节的，就至关重要。我们研究了一个生长因子受体家族，并确定了一个关键的调节子宫内膜的生长和生存的植入胚胎。此外，我们使用无偏见的方法来确定哪些信号通路和遗传网络在该受体下游被激活，以执行成功怀孕所必需的每个过程。了解妊娠调节的机制和遗传网络是开发有效药物治疗的先决条件。
Infertility and adverse gynecological outcomes such as preeclampsia and miscarriage represent significant female reproductive health concerns. The spatiotemporal expression of growth factors indicates that they play an important role in pregnancy. The goal of this study is to define the role of the ERBB family of growth factor receptors in endometrial function. Using conditional ablation in mice and siRNA in primary human endometrial stromal cells, we identified the epidermal growth factor receptor (Egfr) to be critical for endometrial function during early pregnancy. While ablation of Her2 or Erbb3 led to only a modest reduction in litter size, mice lacking Egfr expression are severely subfertile. Pregnancy demise occurred shortly after blastocyst implantation due to defects in decidualization including decreased proliferation, cell survival, differentiation and target gene expression. To place Egfr in a genetic regulatory hierarchy, transcriptome analyses was used to compare the gene signatures from mice with conditional ablation of Egfr, wingless-related MMTV integration site 4 (Wnt4) or boneless morphogenic protein 2 (Bmp2); revealing that not only are Bmp2 and Wnt4 key downstream effectors of Egfr, but they also regulate distinct physiological functions. In primary human endometrial stromal cells, marker gene expression, a novel high content image-based approach and phosphokinase array analysis were used to demonstrate that EGFR is a critical regulator of human decidualization. Furthermore, inhibition of EGFR signaling intermediaries WNK1 and AKT1S1, members identified in the kinase array and previously unreported to play a role in the endometrium, also attenuate decidualization. These results demonstrate that EGFR plays an integral role in establishing the cellular context necessary for successful pregnancy via the activation of intricate signaling and transcriptional networks, thereby providing valuable insight into potential therapeutic targets. Approximately 10% of reproductive aged women are considered infertile. While great strides have been made in assisted reproductive technologies, overall success rates, especially considering the cost, remain low. Studies indicate that due to its sequential nature, nearly 75% of pregnancy failures are due to defects that occur very early in gestation. Therefore, understanding the physiological changes that occur in the endometrium during this period and how those changes are regulated is of paramount importance if we are to improve our ability to address female reproductive health concerns. We investigated a family of growth factor receptors and identified one that critically regulates the growth and survival of the endometrium in response to the implanting embryo. Furthermore, we used unbiased approaches to identify which signaling pathways and genetic networks are activated downstream of this receptor to execute each of the processes necessary for a successful pregnancy. Understanding the mechanisms and genetic networks with which pregnancy is regulated is a prerequisite to the development of effective pharmaceutical therapeutics.
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