Neonatal maternal separation alters the capacity of adult neural precursor cells to differentiate into neurons via methylation of retinoic acid receptor gene promoter.
Neonatal maternal separation alters the capacity of adult neural precursor cells to differentiate into neurons via methylation of retinoic acid receptor gene promoter.
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DOI：
10.1016/j.biopsych.2014.07.008
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发表时间：
2015-02-15
影响因子：
10.6
通讯作者：
Kusumi I
中科院分区：
文献类型：
--
作者：
Boku S;Toda H;Nakagawa S;Kato A;Inoue T;Koyama T;Hiroi N;Kusumi I
早期生活压力被认为会导致精神疾病，但这种联系背后的确切机制却知之甚少。由于新生儿应激降低了成年海马神经发生，这反过来又在功能上有助于许多与精神疾病相关的行为表型，我们研究了体内新生儿母亲分离（NMS）如何通过体外表观遗传改变影响成年海马神经前体细胞的能力。从出生后第2天（PND）至PND第14天，每天将大鼠幼仔与其母体分离3小时，或从未与母体分离（作为对照动物）。我们在PND 56时从海马齿状回分离成年神经前体细胞，并评估细胞培养中的增殖、凋亡和分化率。我们还评估了源于NMS的视黄酸受体（RAR）启动子DNA甲基化对成体神经前体细胞的影响。NMS减弱了成体神经前体细胞的神经分化，但对增殖、凋亡或星形胶质细胞分化没有可检测的影响。DNA甲基转移酶（DNMT）抑制剂，5-aza-dC，逆转了NMS对成年神经前体细胞神经分化的抑制作用。NMS增加DNMT 1表达，降低RARα表达。RARα激动剂增加神经分化，拮抗剂减少视黄酸诱导的神经分化。NMS增加了RARα启动子的甲基化部分，DNMT抑制剂逆转了NMS对RARα信使RNA表达的降低。NMS通过DNMT 1介导的RARα启动子甲基化降低RARα表达，从而减弱成年海马神经前体细胞向神经元分化的能力。
Early life stress is thought to contribute to psychiatric disorders, but the precise mechanisms underlying this link are poorly understood. As neonatal stress decreases adult hippocampal neurogenesis, which, in turn, functionally contributes to many behavioral phenotypes relevant to psychiatric disorders, we examined how in vivo neonatal maternal separation (NMS) impacts the capacity of adult hippocampal neural precursor cells via epigenetic alterations in vitro. Rat pups were separated from their dams for 3 hours daily from postnatal day (PND) 2 to PND 14 or were never separated from the dam (as control animals). We isolated adult neural precursor cells from the hippocampal dentate gyrus at PND 56 and assessed rates of proliferation, apoptosis, and differentiation in cell culture. We also evaluated the effect of DNA methylation at the retinoic acid receptor (RAR) promoter stemming from NMS on adult neural precursor cells. NMS attenuated neural differentiation of adult neural precursor cells but had no detectible effect on proliferation, apoptosis, or astroglial differentiation. The DNA methyltransferase (DNMT) inhibitor, 5-aza-dC, reversed a reduction by NMS of neural differentiation of adult neural precursor cells. NMS increased DNMT1 expression and decreased expression of RARα. An RARα agonist increased neural differentiation and an antagonist reduced retinoic acid-induced neural differentiation. NMS increased the methylated portion of RARα promoter, and the DNMT inhibitor reversed a reduction by NMS of RARα messenger RNA expression. NMS attenuates the capacity of adult hippocampal neural precursor cells to differentiate into neurons by decreasing expression of RARα through DNMT1-mediated methylation of its promoter.