: 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.

A tripartite circRNA/mRNA/miRNA interaction regulates glutamatergic signaling in the mouse brain / Silenzi, Valentina; D'Ambra, Eleonora; Santini, Tiziana; D'Uva, Sara; Setti, Adriano; Salvi, Nicolò; Nicoletti, Carmine; Scarfò, Rebecca; Cordella, Federica; Mongiardi, Brunella; Cavezza, Diletta; Liessi, Nara; Ferrucci, Laura; Ragozzino, Davide; Armirotti, Andrea; Di Angelantonio, Silvia; De Leonibus, Elvira; Bozzoni, Irene; Morlando, Mariangela. - In: CELL REPORTS. - ISSN 2211-1247. - 43:10(2024), pp. 1-28. [10.1016/j.celrep.2024.114766]

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

Silenzi, Valentina;D'Ambra, Eleonora;Santini, Tiziana;D'Uva, Sara;Setti, Adriano;Salvi, Nicolò;Nicoletti, Carmine;Cordella, Federica;Cavezza, Diletta;Ferrucci, Laura;Ragozzino, Davide;Di Angelantonio, Silvia;De Leonibus, Elvira;Bozzoni, Irene
Penultimo
Funding Acquisition
;
Morlando, Mariangela
Ultimo
Funding Acquisition
2024

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.
2024
AMPA; molecular biology; neuroscience; CRISPR/Cas9; RNA localization; RNA-RNA interaction; circRNA; glutamatergic signaling; microRNA; mouse embryonic stem cells; striatum
01 Pubblicazione su rivista::01a Articolo in rivista
A tripartite circRNA/mRNA/miRNA interaction regulates glutamatergic signaling in the mouse brain / Silenzi, Valentina; D'Ambra, Eleonora; Santini, Tiziana; D'Uva, Sara; Setti, Adriano; Salvi, Nicolò; Nicoletti, Carmine; Scarfò, Rebecca; Cordella, Federica; Mongiardi, Brunella; Cavezza, Diletta; Liessi, Nara; Ferrucci, Laura; Ragozzino, Davide; Armirotti, Andrea; Di Angelantonio, Silvia; De Leonibus, Elvira; Bozzoni, Irene; Morlando, Mariangela. - In: CELL REPORTS. - ISSN 2211-1247. - 43:10(2024), pp. 1-28. [10.1016/j.celrep.2024.114766]
File allegati a questo prodotto
File Dimensione Formato  
Silenzi_Tripartite_2024.pdf

accesso aperto

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Creative commons
Dimensione 5.07 MB
Formato Adobe PDF
5.07 MB Adobe PDF

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1720188
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact