Senís, ElenaEsgleas, MiriamNajas Sales, Sònia, 1985-Jiménez-Sábado, VerónicaBertani, CamillaGiménez-Alejandre, MartaEscriche, AlbaRuiz Orera, Jorge, 1988-Hergueta-Redondo, MartaJiménez, MireiaGiralt, AlbertNuciforo, Paolo G.Albà Soler, MarPeinado, HéctorToro, DanielHove-Madsen, LeifGötz, MagdalenaAbad, María2022-09-192022-09-192021Senís E, Esgleas M, Najas S, Jiménez-Sábado V, Bertani C, Giménez-Alejandre M, Escriche A, Ruiz-Orera J, Hergueta-Redondo M, Jiménez M, Giralt A, Nuciforo P, Albà MM, Peinado H, Del Toro D, Hove-Madsen L, Götz M, Abad M. TUNAR lncRNA encodes a microprotein that regulates neural differentiation and neurite formation by modulating calcium dynamics. Front Cell Dev Biol. 2021 Dec 31;9:747667. DOI: 10.3389/fcell.2021.7476672296-634Xhttp://hdl.handle.net/10230/54101Long noncoding RNAs (lncRNAs) are regulatory molecules which have been traditionally considered as "non-coding". Strikingly, recent evidence has demonstrated that many non-coding regions, including lncRNAs, do in fact contain small-open reading frames that code for small proteins that have been called microproteins. Only a few of them have been characterized so far, but they display key functions in a wide variety of cellular processes. Here, we show that TUNAR lncRNA encodes an evolutionarily conserved microprotein expressed in the nervous system that we have named pTUNAR. pTUNAR deficiency in mouse embryonic stem cells improves their differentiation potential towards neural lineage both in vitro and in vivo. Conversely, pTUNAR overexpression impairs neuronal differentiation by reduced neurite formation in different model systems. At the subcellular level, pTUNAR is a transmembrane protein that localizes in the endoplasmic reticulum and interacts with the calcium transporter SERCA2. pTUNAR overexpression reduces cytoplasmatic calcium, consistent with a possible role of pTUNAR as an activator of SERCA2. Altogether, our results suggest that our newly discovered microprotein has an important role in neural differentiation and neurite formation through the regulation of intracellular calcium. From a more general point of view, our results provide a proof of concept of the role of lncRNAs-encoded microproteins in neural differentiation.application/pdfeng© 2021 Senís, Esgleas, Najas, Jiménez-Sábado, Bertani, Giménez-Alejandre, Escriche, Ruiz-Orera, Hergueta-Redondo, Jiménez, Giralt, Nuciforo, Albà, Peinado, Toro, Hove-Madsen, Götz and Abad. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.info:eu-repo/semantics/articlehttp://dx.doi.org/10.3389/fcell.2021.747667TUNARCalciumLong non-coding RNAsMicropeptidesMicroproteinsNeural differentiationNeurite formationsORF encoded peptidesinfo:eu-repo/semantics/openAccess