Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, 00185 Rome, Italy.
Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, 00185 Rome, Italy; Center for Life Nano- & Neuro-Science@Sapienza of Istituto Italiano di Tecnologia (IIT), 00161 Rome, Italy.
Cell Rep. 2024 Oct 22;43(10):114766. doi: 10.1016/j.celrep.2024.114766. Epub 2024 Sep 24.
Functional studies of circular RNAs (circRNAs) began quite recently, and few data exist on their function in vivo. Here, we have generated a knockout (KO) mouse model to study circDlc1(2), a circRNA highly expressed in the prefrontal cortex and striatum. The loss of circDlc1(2) led to the upregulation of glutamatergic-response-associated genes in the striatal tissue, enhanced excitatory synaptic transmission in neuronal cultures, and hyperactivity and increased stereotypies in mice. Mechanistically, we found that circDlc1(2) physically interacts with some mRNAs, associated with glutamate receptor signaling (gluRNAs), and with miR-130b-5p, a translational regulator of these transcripts. Notably, differently from canonical microRNA (miRNA) "sponges," circDlc1(2) synergizes with miR-130b-5p to repress gluRNA expression. We found that circDlc1(2) is required to spatially control miR-130b-5p localization at synaptic regions where gluRNA is localized, indicating a different layer of regulation where circRNAs ensure robust control of gene expression via the correct subcellular compartmentalization of functionally linked interacting partners.
环状 RNA (circRNAs) 的功能研究最近才开始，关于它们在体内的功能知之甚少。在这里，我们生成了一个敲除 (KO) 小鼠模型来研究 circDlc1(2)，这是一种在前脑皮层和纹状体中高度表达的环状 RNA。circDlc1(2) 的缺失导致纹状体组织中谷氨酸能反应相关基因的上调，增强神经元培养物中的兴奋性突触传递，以及小鼠的多动和刻板行为增加。从机制上讲，我们发现 circDlc1(2) 与一些与谷氨酸受体信号转导 (gluRNAs) 相关的 mRNAs 以及翻译这些转录物的 miR-130b-5p 发生物理相互作用。值得注意的是，与经典的 microRNA (miRNA) “海绵”不同，circDlc1(2) 与 miR-130b-5p 协同作用以抑制 gluRNA 的表达。我们发现 circDlc1(2) 是空间控制 miR-130b-5p 在突触区域定位所必需的，其中定位 gluRNA，表明circRNAs 通过功能相关相互作用伙伴的正确细胞区室化来确保基因表达的稳健控制的不同调控层。
