@ARTICLE{10.3389/fcell.2021.747667, AUTHOR={Senís, Elena and Esgleas, Miriam and Najas, Sonia and Jiménez-Sábado, Verónica and Bertani, Camilla and Giménez-Alejandre, Marta and Escriche, Alba and Ruiz-Orera, Jorge and Hergueta-Redondo, Marta and Jiménez, Mireia and Giralt, Albert and Nuciforo, Paolo and Albà, M. Mar and Peinado, Héctor and Toro, Daniel del and Hove-Madsen, Leif and Götz, Magdalena and Abad, María}, TITLE={TUNAR lncRNA Encodes a Microprotein that Regulates Neural Differentiation and Neurite Formation by Modulating Calcium Dynamics}, JOURNAL={Frontiers in Cell and Developmental Biology}, VOLUME={9}, YEAR={2021}, URL={https://www.frontiersin.org/articles/10.3389/fcell.2021.747667}, DOI={10.3389/fcell.2021.747667}, ISSN={2296-634X}, ABSTRACT={Long 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.} }