Nrk, an X-linked Protein Kinase in the Germinal Center Kinase Family, Is Required for Placental Development and Fetoplacental Induction of Labor
Nrk, an X-linked Protein Kinase in the Germinal Center Kinase Family, Is Required for Placental Development and Fetoplacental Induction of Labor
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DOI：
10.1074/jbc.m111.258160
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发表时间：
2011-08-19
影响因子：
4.8
通讯作者：
Komada, Masayuki
中科院分区：
文献类型：
--
作者：
Denda, Kimitoshi;Nakao-Wakabayashi, Kanako;Komada, Masayuki
真兽目哺乳动物引产的完整机制尚不清楚。虽然已经提出胎儿和胎盘在触发分娩中的重要作用，但没有显示胎儿/胎盘中需要用于引产的基因。在这里，我们表明，Nrk，一个X-连锁基因编码的丝氨酸/苏氨酸激酶的germinal中心激酶家族，是必不可少的胎儿/胎盘在小鼠的劳动。Nrk特异性表达于海绵滋养层（胎盘的胎儿来源区域），Nrk破坏导致该层过度生长失调。由于父源性X染色体在胎盘中的优先失活，当野生型等位基因是父源性时，Nrk杂合突变胎盘表现出与Nrk缺失组织中类似的缺陷。然而，由于失活X染色体的Nrk表达泄漏，表型比Nrk缺失胎盘弱。Nrk缺失雌性与野生型和Nrk缺失雄性的杂交，以及Nrk缺失胎儿与野生型雌性的子宫转移，揭示了当所有胎儿/胎盘都是Nrk缺失时，妊娠小鼠表现出严重的分娩缺陷。此外，Nrk在妊娠小鼠的雌性生殖组织如子宫和卵巢以及胎儿羊膜和卵黄囊中不表达。母体循环和胎盘中控制分娩时间的孕激素和雌激素水平不受Nrk干扰的影响。因此，我们提供了一种新的劳动诱导胎儿胎盘信号，依赖于X染色体，可能来自胎盘的证据。
The complete mechanism of labor induction in eutherian mammals remains unclear. Although important roles for the fetus and placenta in triggering labor have been proposed, no gene has been shown to be required in the fetus/placenta for labor induction. Here we show that Nrk, an X-linked gene encoding a Ser/Thr kinase of the germinal center kinase family, is essential in the fetus/placenta for labor in mice. Nrk was specifically expressed in the spongiotrophoblast layer, a fetus-derived region of the placenta, and Nrk disruption caused dysregulated overgrowth of the layer. Due to preferential inactivation of the paternally derived X chromosome in placenta, Nrk heterozygous mutant placentas exhibited a similar defect to that in Nrk-null tissues when the wild-type allele was paternally derived. However, the phenotype was weaker than in Nrk-null placentas due to leaky Nrk expression from the inactivated X chromosome. Crossing of Nrk-null females to wild-type and Nrk-null males, as well as uterine transfer of Nrk-null fetuses to wild-type females, revealed that pregnant mice exhibit a severe defect in delivery when all fetuses/placentas are Nrk-null. In addition, Nrk was not expressed in female reproductive tissues such as the uterus and ovary, as well as the fetal amnion and yolk sac, in pregnant mice. Progesterone and estrogen levels in the maternal circulation and placenta, which control the timing of labor, were unaffected upon Nrk disruption. We thus provide evidence for a novel labor-inducing fetoplacental signal that depends on the X chromosome and possibly arises from the placenta.