Institute for Physiological Chemistry, Biochemical-Pharmacological Center Marburg, Philipps-University of Marburg, Marburg, Germany
Institute for Physiological Chemistry, Biochemical-Pharmacological Center Marburg, Philipps-University of Marburg, Marburg, Germany.
EMBO Rep. 2018 Mar;19(3). doi: 10.15252/embr.201744853. Epub 2017 Dec 20.
MicroRNAs are important regulators of local protein synthesis during neuronal development. We investigated the dynamic regulation of microRNA production and found that the majority of the microRNA-generating complex, consisting of Dicer, TRBP, and PACT, specifically associates with intracellular membranes in developing neurons. Stimulation with brain-derived neurotrophic factor (BDNF), which promotes dendritogenesis, caused the redistribution of TRBP from the endoplasmic reticulum into the cytoplasm, and its dissociation from Dicer, in a Ca-dependent manner. As a result, the processing of a subset of neuronal precursor microRNAs, among them the dendritically localized pre-miR16, was impaired. Decreased production of miR-16-5p, which targeted the BDNF mRNA itself, was rescued by expression of a membrane-targeted TRBP Moreover, miR-16-5p or membrane-targeted TRBP expression blocked BDNF-induced dendritogenesis, demonstrating the importance of neuronal TRBP dynamics for activity-dependent neuronal development. We propose that neurons employ specialized mechanisms to modulate local gene expression in dendrites, via the dynamic regulation of microRNA biogenesis factors at intracellular membranes of the endoplasmic reticulum, which in turn is crucial for neuronal dendrite complexity and therefore neuronal circuit formation and function.
微小 RNA 是神经元发育过程中局部蛋白质合成的重要调节因子。我们研究了微小 RNA 产生的动态调节，发现由 Dicer、TRBP 和 PACT 组成的大多数微小 RNA 生成复合物特异性地与发育中的神经元的细胞内膜结合。脑源性神经营养因子（BDNF）的刺激促进树突发生，导致 TRBP 从内质网以 Ca2+依赖性方式重新分布到细胞质中，并与 Dicer 解离。结果，一小部分神经元前体微小 RNA 的加工受到损害，其中包括定位于树突的 pre-miR16。通过表达靶向 TRBP 的膜定位，可以挽救 miR-16-5p 的产生减少，其靶向 BDNF mRNA 本身。此外，miR-16-5p 或膜靶向 TRBP 的表达阻断了 BDNF 诱导的树突发生，证明神经元 TRBP 动力学对于活性依赖性神经元发育至关重要。我们提出，神经元通过内质网细胞内膜上微小 RNA 生物发生因子的动态调节，利用专门的机制来调节树突中的局部基因表达，这对于神经元树突复杂性以及因此神经元回路的形成和功能至关重要。
