Hoxa-10 deficiency alters region-specific gene expression and perturbs differentiation of natural killer cells during decidualization.
Hoxa-10 deficiency alters region-specific gene expression and perturbs differentiation of natural killer cells during decidualization.
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DOI：
10.1016/j.ydbio.2005.11.016
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发表时间：
2006-02
影响因子：
2.7
通讯作者：
M. Rahman;Meiling Li;Ping Li;Haibin Wang;S. Dey;S. Das
中科院分区：
文献类型：
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作者：
M. Rahman;Meiling Li;Ping Li;Haibin Wang;S. Dey;S. Das
子宫蜕膜化是成功着床的关键事件，受到基质细胞增殖和分化的严格控制。蜕膜化的一个标志性事件是通过在植入部位的抗子宫内膜极的终末分化获得基质细胞多倍体。 Hoxa-10 是一种发育调节的同源框转录因子，在蜕膜基质细胞中高表达，小鼠中 Hoxa-10 的靶向缺失显示出严重的蜕膜缺陷，这主要是由于基质细胞对孕酮的反应性降低。然而，Hoxa-10 调节这一过程的潜在分子机制仍然很大程度上未知。在这里，我们发现 Hoxa-10 缺陷会导致基质细胞增殖过程中核心细胞周期活性减弱，而不会干扰多倍体，这表明这些事件取决于影响细胞周期机制的局部调节因子。为了进一步解决这个问题，我们比较了诱导蜕膜化后野生型和 Hoxa-10−/− 小鼠子宫中的整体基因表达谱。我们的研究表明 Hoxa-10 下游蜕膜化的两个主要方面。首先，Hoxa-10 缺陷导致细胞周期蛋白依赖性激酶 4 (cdk4) 和 -6 (cdk6)、生长分化因子 10 (Gdf10)、肝细胞生长因子 (Hgf) 和 Snail2 的异常区域特异性表达。其次，Hoxa-10 缺陷会损害自然杀伤 (NK) 细胞的分化，但不会改变蜕膜化过程中 NK 前体细胞的运输。总的来说，这些结果提供了证据，证明 Hoxa-10 影响着床后时期繁殖正常蜕膜发育所必需的许多基因和细胞功能。
Uterine decidualization, a key event for successful implantation, is critically controlled by stromal cell proliferation and differentiation. One hallmark event of decidualization is the acquisition of stromal cell polyploidy through terminal differentiation at the anti-mesometrial pole of the implantation site. Hoxa-10, a developmentally regulated homeobox transcription factor, is highly expressed in decidualizing stromal cells, and targeted deletion of Hoxa-10 in mice shows severe decidualization defects, primarily due to reduced stromal cell responsiveness to progesterone. However, the underlying molecular mechanism by which Hoxa-10 regulates this process remains largely unknown. Here, we show that Hoxa-10 deficiency confers diminished core cell cycle activity during stromal cell proliferation without disturbing polyploidy, suggesting that these events depend on local regulators that impact cell cycle machinery. To further address this question, we compared global gene expression profiles in uteri of wild-type and Hoxa-10−/−mice after inducing decidualization. Our studies show two major aspects of decidualization downstream of Hoxa-10. First, Hoxa-10 deficiency results in the aberrant region-specific expression of cyclin-dependent kinase-4 (cdk4) and -6 (cdk6), growth differentiation factor 10 (Gdf10), hepatocyte growth factor (Hgf) and Snail2. Second, Hoxa-10 deficiency compromises natural killer (NK) cell differentiation without altering trafficking of NK precursor cells during decidualization. Collectively, the results provide evidence that Hoxa-10 influences a host of genes and cell functions necessary for propagating normal decidual development during the post-implantation period.