The hypothalamic-pituitary-adrenal (HPA) axis plays a principal role in stress response regulation and has been implicated in the etiology of stress-related disorders. The HPA axis regulates the normal synthesis and release of glucocorticoids; dysregulation of the HPA axis causes abnormal responses to stress. FK506-binding protein 5 (FKBP5), a co-chaperone of heat shock protein 90 in the glucocorticoid receptor (GR) molecular complex, is a key GR sensitivity regulator. FKBP5 single nucleotide polymorphisms are associated with dysregulated HPA axis and increased risk of stress-related disorders, including posttraumatic stress disorder (PTSD) and depression. In this study, we profiled the microRNAs (miRNAs) in the medial prefrontal cortex of Fkbp5 knockout (Fkbp5-/- ) mice and identified the target genes of differentially expressed miRNAs using sequence-based miRNA target prediction. Gene ontology analysis revealed that the differentially expressed miRNAs were involved in nervous system development, regulation of cell migration, and intracellular signal transduction. The validation of the expression of predicted target genes using quantitative polymerase chain reaction revealed that the expression of axon development-related genes, specifically actin-binding LIM protein 1 (Ablim1), lemur tyrosine kinase 2 (Lmtk2), kinesin family member 5c (Kif5c), neurofascin (Nfasc), and ephrin type-A receptor 4 (Epha4), was significantly decreased, while that of brain-derived neurotrophic factor (Bdnf) was significantly increased in the brain of Fkbp5-/- mice. These results suggest that axonal development-related genes can serve as potential targets in future studies focused on understanding the pathophysiology of PTSD.

中文翻译：

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Fkbp5基因敲除小鼠内侧前额叶皮质髓鞘形成缺陷

下丘脑-垂体-肾上腺 (HPA) 轴在压力反应调节中起主要作用，并与压力相关疾病的病因有关。HPA 轴调节糖皮质激素的正常合成和释放；HPA 轴的失调导致对压力的异常反应。FK506 结合蛋白 5 (FKBP5) 是糖皮质激素受体 (GR) 分子复合物中热休克蛋白 90 的共同伴侣，是关键的 GR 敏感性调节剂。FKBP5 单核苷酸多态性与失调的 HPA 轴和压力相关疾病的风险增加有关，包括创伤后应激障碍 (PTSD) 和抑郁症。在这项研究中，我们分析了 Fkbp5 敲除 (Fkbp5-/-) 小鼠内侧前额叶皮层中的 microRNA (miRNA)，并使用基于序列的 miRNA 靶标预测鉴定了差异表达的 miRNA 的靶基因。基因本体分析表明，差异表达的miRNAs参与神经系统发育、细胞迁移调控和细胞内信号转导。使用定量聚合酶链反应验证预测靶基因的表达表明轴突发育相关基因的表达，特别是肌动蛋白结合 LIM 蛋白 1 (Ablim1)、狐猴酪氨酸激酶 2 (Lmtk2)、驱动蛋白家族成员 5c (Kif5c )、神经成束蛋白 (Nfasc) 和 ephrin A 型受体 4 (Epha4) 显着降低，而脑源性神经营养因子（Bdnf）在 Fkbp5-/- 小鼠大脑中的含量显着增加。这些结果表明轴突发育相关基因可以作为未来研究的潜在目标，重点是了解 PTSD 的病理生理学。