ciRS-7 and miR-7 regulate ischemia-induced neuronal death via glutamatergic signaling
Flavia Scoyni, Valeriia Sitnikova, Luca Giudice, Paula Korhonen, Davide M Trevisan, Ana Hernández de Sande, Mireia Gómez‐Budia, Raisa Giniatullina, Irene F. Ugidos, Hiramani Dhungana, Cristiana Pistono, Nea Korvenlaita, Nelli‐Noora Välimäki, Salla M. Kangas, Anniina E. Hiltunen, Emma S. Gribchenko, Minna U. Kaikkonen, Jari Koıstınaho, Seppo Ylä‐Herttuala, Reetta Hinttala, Morten T. Venø, Junyi Su, Markus Stoffel, Anne Schaefer, Nikolaus Rajewsky, Jørgen Kjems, Mary P. LaPierre, Monika Piwecka, Jukka Jolkkonen, Rashid Giniatullin, Thomas B. Hansen, Tarja Malm
Abstract
Brain functionality relies on finely tuned regulation of gene expression by networks of non-coding RNAs (ncRNAs) such as the one composed by the circular RNA ciRS-7 (also known as CDR1as), the microRNA miR-7, and the long ncRNA Cyrano. We describe ischemia-induced alterations in the ncRNA network both in vitro and in vivo and in transgenic mice lacking ciRS-7 or miR-7. Our data show that cortical neurons downregulate ciRS-7 and Cyrano and upregulate miR-7 expression during ischemia. Mice lacking ciRS-7 exhibit reduced lesion size and motor impairment, while the absence of miR-7 alone results in increased ischemia-induced neuronal death. Moreover, miR-7 levels in pyramidal excitatory neurons regulate neurite morphology and glutamatergic signaling, suggesting a potential molecular link to the in vivo phenotype. Our data reveal the role of ciRS-7 and miR-7 in modulating ischemic stroke outcome, shedding light on the pathophysiological function of intracellular ncRNA networks in the brain.