Störchel Peter H, Thümmler Juliane, Siegel Gabriele, Aksoy-Aksel Ayla, Zampa Federico, Sumer Simon, Schratt Gerhard
Institute for Physiological Chemistry Biochemical-Pharmacological Center Marburg Philipps-University Marburg, Marburg, Germany.
Institute for Physiological Chemistry Biochemical-Pharmacological Center Marburg Philipps-University Marburg, Marburg, Germany
EMBO J. 2015 Sep 2;34(17):2237-54. doi: 10.15252/embj.201490643. Epub 2015 Jun 23.
MicroRNAs (miRNAs) are important regulators of neuronal development, network connectivity, and synaptic plasticity. While many neuronal miRNAs were previously shown to modulate neuronal morphogenesis, little is known regarding the regulation of miRNA function. In a large-scale functional screen, we identified two novel regulators of neuronal miRNA function, Nova1 and Ncoa3. Both proteins are expressed in the nucleus and the cytoplasm of developing hippocampal neurons. We found that Nova1 and Ncoa3 stimulate miRNA function by different mechanisms that converge on Argonaute (Ago) proteins, core components of the miRNA-induced silencing complex (miRISC). While Nova1 physically interacts with Ago proteins, Ncoa3 selectively promotes the expression of Ago2 at the transcriptional level. We further show that Ncoa3 regulates dendritic complexity and dendritic spine maturation of hippocampal neurons in a miRNA-dependent fashion. Importantly, both the loss of miRNA activity and increased dendrite complexity upon Ncoa3 knockdown were rescued by Ago2 overexpression. Together, we uncovered two novel factors that control neuronal miRISC function at the level of Ago proteins, with possible implications for the regulation of synapse development and plasticity.
微小RNA（miRNA）是神经元发育、网络连接和突触可塑性的重要调节因子。虽然先前已证明许多神经元miRNA可调节神经元形态发生，但对于miRNA功能的调控却知之甚少。在一项大规模功能筛选中，我们鉴定出了神经元miRNA功能的两个新调节因子，Nova1和Ncoa3。这两种蛋白均在发育中的海马神经元的细胞核和细胞质中表达。我们发现Nova1和Ncoa3通过不同机制刺激miRNA功能，这些机制都汇聚于AGO蛋白，即miRNA诱导沉默复合体（miRISC）的核心成分。虽然Nova1与AGO蛋白发生物理相互作用，但Ncoa3在转录水平上选择性地促进Ago2的表达。我们进一步表明，Ncoa3以miRNA依赖的方式调节海马神经元的树突复杂性和树突棘成熟。重要的是，Ago2的过表达挽救了miRNA活性丧失以及Ncoa3敲低后树突复杂性增加的情况。总之，我们发现了两个在AGO蛋白水平控制神经元miRISC功能的新因子，这可能对突触发育和可塑性的调控具有重要意义。
