Zampa Federico, Bicker Silvia, Schratt Gerhard
Institute of Physiological Chemistry, Philipps-University Marburg, Marburg, Germany.
Front Mol Neurosci. 2018 Jun 11;11:171. doi: 10.3389/fnmol.2018.00171. eCollection 2018.
microRNAs (miRNAs) have emerged as critical regulators of neuronal dendrite development. Specific precursor (pre-)miRNAs are actively transported to dendrites, but whether this process is regulated by neuronal activity and involved in activity-dependent dendritogenesis is unknown. Here we show that BDNF, a neurotrophin that is released in response to increased neuronal activity, promotes dendritic accumulation of pre-miR-134. Dendritic accumulation, but not transcription of pre-miR-134, is abrogated by treatment of neurons with the NMDA receptor (NMDAR) antagonist APV. Furthermore, APV interferes with BDNF-mediated repression of the known miR-134 target Pumilio 2 (Pum2) in a miR-134 binding site-specific manner. At the functional level, both APV treatment and knockdown of the pre-miR-134 transport protein DHX36 antagonize BDNF-induced dendritogenesis. These effects are likely mediated by reduced dendritic miR-134 activity, since both transfection of a synthetic miR-134 duplex or of a dendritically targeted pre-miR-134-181a chimera rescues BDNF-dependent dendritogenesis in the presence of APV. In conclusion, we have identified a novel NMDAR-dependent mechanism involved in the activity-dependent control of miRNA function during neuronal development.
微小RNA（miRNA）已成为神经元树突发育的关键调节因子。特定的前体（pre-）miRNA会被主动运输到树突中，但这一过程是否受神经元活动调控以及是否参与依赖活动的树突形成尚不清楚。在此，我们表明脑源性神经营养因子（BDNF），一种响应神经元活动增加而释放的神经营养因子，可促进前体miR-134在树突中的积累。用N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂APV处理神经元可消除前体miR-134在树突中的积累，但不会影响其转录。此外，APV以miR-134结合位点特异性的方式干扰BDNF介导的对已知miR-134靶标Pumilio 2（Pum2）的抑制作用。在功能水平上，APV处理和前体miR-134转运蛋白DHX36的敲低均拮抗BDNF诱导的树突形成。这些效应可能是由树突中miR-134活性降低介导的，因为在存在APV的情况下，转染合成的miR-134双链体或树突靶向的前体miR-134-181a嵌合体均可挽救BDNF依赖的树突形成。总之，我们确定了一种新的NMDAR依赖性机制，该机制参与神经元发育过程中miRNA功能的活动依赖性控制。
