1. A tripartite circRNA/mRNA/miRNA interaction regulates glutamatergic signaling in the mouse brain.
- Author
-
Silenzi V, D'Ambra E, Santini T, D'Uva S, Setti A, Salvi N, Nicoletti C, Scarfò R, Cordella F, Mongiardi B, Cavezza D, Liessi N, Ferrucci L, Ragozzino D, Armirotti A, Di Angelantonio S, De Leonibus E, Bozzoni I, and Morlando M
- Subjects
- Animals, Mice, RNA metabolism, RNA genetics, Brain metabolism, Receptors, Glutamate metabolism, Receptors, Glutamate genetics, Glutamic Acid metabolism, Mice, Inbred C57BL, Neurons metabolism, MicroRNAs metabolism, MicroRNAs genetics, RNA, Circular metabolism, RNA, Circular genetics, RNA, Messenger metabolism, RNA, Messenger genetics, Signal Transduction, Mice, Knockout
- Abstract
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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF