MicroRNA-137 regulates a glucocorticoid receptor-dependent signalling network: implications for the etiology of schizophrenia.
MicroRNA-137 regulates a glucocorticoid receptor-dependent signalling network: implications for the etiology of schizophrenia.
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DOI：
10.1503/jpn.130269
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发表时间：
2014
期刊：
影响因子：
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通讯作者：
A. Vallès;G. Martens;P. De Weerd;G. Poelmans;A. Aschrafi
中科院分区：
文献类型：
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作者：
A. Vallès;G. Martens;P. De Weerd;G. Poelmans;A. Aschrafi
背景精神分裂症是一种高度遗传性的神经发育障碍。 microRNA-137 (miR-137) 的遗传变体与精神分裂症在全基因组范围内产生了显着的关联，表明该 miRNA 在其病因学中发挥着关键作用。因此，相互作用的 miR-137 靶标的分子网络可能有助于深入了解精神分裂症的生物学过程。方法我们首先使用生物信息学工具来获取和分析预测的人类和小鼠 miR-137 靶标。然后，我们在环境富集 (EE) 后测定了大鼠桶状皮质中的 miR-137 水平，环境富集 (EE) 是一种神经元可塑性模型，可诱导几个预测的 miR-137 靶点上调。随后，通过大鼠皮质神经元中 miR-137 功能丧失实验来检查这些预测靶标的表达变化。最后，我们进行了生物信息学和文献分析，以检查 miR-137 下调后上调的靶标。结果预测的人和小鼠 miR-137 靶点在神经元过程中丰富，例如轴突引导、神经突发生和神经传递。 EE 后 miR-137 水平显着下调，我们通过 miR-137 功能丧失实验鉴定了 5 个新的 miR-137 靶点。这些靶点符合糖皮质激素受体依赖性信号传导网络，该网络还包括 3 个已知的 miR-137 靶点，这些靶点与精神分裂症在全基因组范围内显着相关。局限性 由于缺乏预测大鼠 miR-137 靶点的信息，生物信息学分析涉及预测的人类和小鼠 miR-137 靶点，而后续实验是在大鼠身上进行的。此外，不能排除 miR-137 功能丧失实验中的间接影响。结论 我们已经确定了 miR-137 调节的蛋白网络，有助于我们了解精神分裂症的分子基础，并为未来精神分裂症精神药理学治疗的研究提供线索。
BACKGROUND Schizophrenia is a highly heritable neurodevelopmental disorder. A genetic variant of microRNA-137 (miR-137) has yielded significant genome-wide association with schizophrenia, suggesting that this miRNA plays a key role in its etiology. Therefore, a molecular network of interacting miR-137 targets may provide insights into the biological processes underlying schizophrenia. METHODS We first used bioinformatics tools to obtain and analyze predicted human and mouse miR-137 targets. We then determined miR-137 levels in rat barrel cortex after environmental enrichment (EE), a neuronal plasticity model that induces upregulation of several predicted miR-137 targets. Subsequently, expression changes of these predicted targets were examined through loss of miR-137 function experiments in rat cortical neurons. Finally, we conducted bioinformatics and literature analyses to examine the targets that were upregulated upon miR-137 downregulation. RESULTS Predicted human and mouse miR-137 targets were enriched in neuronal processes, such as axon guidance, neuritogenesis and neurotransmission. The miR-137 levels were significantly downregulated after EE, and we identified 5 novel miR-137 targets through loss of miR-137 function experiments. These targets fit into a glucocorticoid receptor-dependent signalling network that also includes 3 known miR-137 targets with genome-wide significant association with schizophrenia. LIMITATIONS The bioinformatics analyses involved predicted human and mouse miR-137 targets owing to lack of information on predicted rat miR-137 targets, whereas follow-up experiments were performed with rats. Furthermore, indirect effects in the loss of miR-137 function experiments cannot be excluded. CONCLUSION We have identified a miR-137-regulated protein network that contributes to our understanding of the molecular basis of schizophrenia and provides clues for future research into psychopharmacological treatments for schizophrenia.