Vallès Astrid, Martens Gerard J M, De Weerd Peter, Poelmans Geert, Aschrafi Armaz
Department of Neurocognition, Faculty of Psychology and Neurosciences, Maastricht University, Maastricht, the Netherlands; Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Nijmegen Centre for Molecular Life Sciences (NCMLS), Radboud University Nijmegen, Nijmegen, the Netherlands.
Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Nijmegen Centre for Molecular Life Sciences (NCMLS), Radboud University Nijmegen, Nijmegen, the Netherlands.
J Psychiatry Neurosci. 2014 Sep;39(5):312-20. doi: 10.1503/jpn.130269.
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.
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.
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.
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.
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.
精神分裂症是一种具有高度遗传性的神经发育障碍。微小RNA - 137（miR - 137）的一种基因变异与精神分裂症在全基因组范围内存在显著关联，这表明该微小RNA在其病因学中起关键作用。因此，相互作用的miR - 137靶标的分子网络可能为深入了解精神分裂症的生物学过程提供线索。
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。然后我们测定了环境富集（EE）后大鼠桶状皮质中的miR - 137水平，环境富集是一种神经元可塑性模型，可诱导上调几个预测的miR - 137靶标。随后，通过在大鼠皮质神经元中进行miR - 137功能缺失实验来检测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，以研究miR - 137下调后上调的靶标。
预测的人类和小鼠miR - 137靶标在神经元过程中富集，如轴突导向、神经突发生和神经传递。EE后miR - 137水平显著下调，并且我们通过miR - 137功能缺失实验鉴定了5个新的miR - 137靶标。这些靶标融入了一个糖皮质激素受体依赖性信号网络，该网络还包括3个已知的与精神分裂症在全基因组范围内存在显著关联的miR - 137靶标。
由于缺乏关于预测的大鼠miR - 137靶标的信息，生物信息学分析涉及预测的人类和小鼠miR - 137靶标，而后续实验是在大鼠中进行的。此外，不能排除miR - 137功能缺失实验中的间接效应。
我们已经鉴定出一个miR - 137调节的蛋白质网络，这有助于我们理解精神分裂症的分子基础，并为未来精神分裂症心理药物治疗的研究提供线索。
