Leucine and arginine regulate trophoblast motility through mTOR-dependent and independent pathways in the preimplantation mouse embryo.
Leucine and arginine regulate trophoblast motility through mTOR-dependent and independent pathways in the preimplantation mouse embryo.
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DOI：
10.1016/j.ydbio.2011.10.021
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发表时间：
2012-01-15
影响因子：
2.7
通讯作者：
Sutherland AE
中科院分区：
文献类型：
--
作者：
González IM;Martin PM;Burdsal C;Sloan JL;Mager S;Harris T;Sutherland AE
子宫着床是哺乳动物繁殖的关键因素，是一个紧密和高度协调的事件。存在一个复杂和相互的子宫-胚胎对话，以同步子宫接受性和伴随的囊胚激活，最大限度地提高着床成功率。虽然在小鼠身上已经发现了许多参与调节子宫容受性的途径，但对胚泡激活的了解较少，胚泡激活是滋养外胚层(TE)接收外部提示的过程，这些提示启动了植入所必需的新特征。氨基酸(AA)在体外对胚泡的激活和运动有调节作用。特别是，我们发现仅精氨酸和亮氨酸是诱导运动的必要条件和充分条件。精氨酸和亮氨酸都单独和相加地作用于传播依赖于哺乳动物雷帕霉素复合体1靶分子(MTORC1)活性的信号。MTORC1、p70S6K和4EBP下游靶分子的活性与滋养层细胞的运动性无关，这表明一条独立的雷帕霉素敏感的途径参与了诱导滋养层细胞的运动性，或者其他平行的氨基酸依赖的途径也参与其中。我们发现，内源性子宫因子在怀孕期间的特定时间诱导mTORC1激活和滋养层运动，并且这个子宫信号晚于先前定义的诱导依附反应的信号。在体内成熟的囊胚表现出对8小时AA刺激的反应能力，激活mTOR，随后在怀孕4.5天早上经历滋养层生长，但在3.5天不是。到第4.5天下午晚些时候，胚胎不再需要任何AA暴露才能在体外经历滋养层细胞的生长，这证明了体内等同信号的存在和时机。这些结果表明，有两个独立的子宫信号调节着床，一个启动胚胎的附着反应，另一个激活mTOR并启动侵袭性行为。
Uterine implantation is a critical element of mammalian reproduction and is a tightly and highly coordinated event. An intricate and reciprocal uterine-embryo dialog exists to synchronize uterine receptivity with the concomitant activation of the blastocyst, maximizing implantation success. While a number of pathways involved in regulating uterine receptivity have been identified in the mouse, less is understood about blastocyst activation, the process by which the trophectoderm (TE) receives extrinsic cues that initiate new characteristics essential for implantation. Amino acids (AA) have been found to regulate blastocyst activation and TE motility in vitro. In particular, we find that arginine and leucine alone are necessary and sufficient to induce TE motility. Both arginine and leucine act individually and additively to propagate signals that are dependent on the activity of the mammalian target of rapamycin complex 1 (mTORC1). The activities of the well-established downstream targets of mTORC1, p70S6K and 4EBP, do not correlate with trophoblast motility, suggesting that an independent-rapamycin-sensitive pathway operates to induce trophoblast motility, or that other, parallel amino acid-dependent pathways are also involved. We find that endogenous uterine factors act to induce mTORC1 activation and trophoblast motility at a specific time during pregnancy, and that this uterine signal is later than the previously defined signal that induces the attachment reaction. In vivo matured blastocysts exhibit competence to respond to an 8-hour AA stimulus by activating mTOR and subsequently undergoing trophoblast outgrowth by the morning of day 4.5 of pregnancy, but not on day 3.5. By the late afternoon of day 4.5, the embryos no longer require any exposure to AA to undergo trophoblast outgrowth in vitro, demonstrating the existence and timing of an equivalent in vivo signal. These results suggest that there are two separate uterine signals regulating implantation, one that primes the embryo for the attachment reaction and another that activates mTOR and initiates invasive behavior.
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DOI：
10.1083/jcb.201007165
发表时间：
2011-01-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ge Y;Sun Y;Chen J
通讯作者：
Chen J
影响因子：
56.9
作者：
BELCHETZ, PE;PLANT, TM;KNOBIL, E
通讯作者：
KNOBIL, E
DOI：
10.1073/pnas.87.21.8212
发表时间：
1990-11-01
影响因子：
11.1
作者：
DEBENEDETTI, A;RHOADS, RE
通讯作者：
RHOADS, RE
影响因子：
4.8
作者：
Franco, Heather L.;Dai, Daisy;DeMayo, Francesco J.
通讯作者：
DeMayo, Francesco J.
影响因子：
2.7
作者：
BORLAND, RM;TASCA, RJ
通讯作者：
TASCA, RJ