A tripartite circRNA/mRNA/miRNA interaction regulates glutamatergic signaling in the mouse brain

• DOI: 10.1016/j.celrep.2024.114766
• Publication Date: 2024-09-24T13:17:52Z
• Authors: Valentina Silenzi; Eleonora D’Ambra; Tiziana Santini; Sara D’Uva; Adriano Setti; Nicolò Salvi; Carmine Nicoletti; Rebecca Scarfò; Federica Cordella; Brunella Mongiardi; Diletta Cavezza; Nara Liessi; Laura Ferrucci; Davide Ragozzino; Andrea Armirotti; Silvia Di Angelan...; Elvira De Leonibus; Irene Bozzoni; Mariangela Morlando
• Keywords: Mice, Knockout; Neurons; microRNA; glutamatergic signaling; striatum; mouse embryonic stem cells; Brain; Glutamic Acid; RNA localization; RNA, Circular; RNA-RNA interaction; Mice, Inbred C57BL; MicroRNAs; Mice; Receptors, Glutamate; CP: Neuroscience; AMPA; Animals; RNA; CP: Molecular biology; circRNA; RNA, Messenger; CRISPR/Cas9; AMPA; molecular biology; neuroscience; CRISPR/Cas9; RNA localization; RNA-RNA interaction; circRNA; glutamatergic signaling; microRNA; mouse embryonic stem cells; striatum; Signal Transduction

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.