Secondary loss of miR-3607 reduced cortical progenitor amplification during rodent evolution

The evolutionary expansion and folding of the mammalian cerebral cortex resulted from amplification of progenitor cells during embryonic development. This process was reversed in the rodent lineage after splitting from primates, leading to smaller and smooth brains. Genetic mechanisms underlying this secondary loss in rodent evolution remain unknown. We show that microRNA miR-3607 is expressed embryonically in the large cortex of primates and ferret, distant from the primate-rodent lineage, but not in mouse. Experimental expression of miR-3607 in embryonic mouse cortex led to increased Wnt/β-catenin signaling, amplification of radial glia cells (RGCs), and expansion of the ventricular zone (VZ), via blocking the β-catenin inhibitor APC (adenomatous polyposis coli). Accordingly, loss of endogenous miR-3607 in ferret reduced RGC proliferation, while overexpression in human cerebral organoids promoted VZ expansion. Our results identify a gene selected for secondary loss during mammalian evolution to limit RGC amplification and, potentially, cortex size in rodents.This work was supported by Santiago Grisolía predoctoral fellowship (K.C.), Generalitat Valenciana I+D+i programs grant APOSTD/2019/059 (A.C.), Fundación Tatiana Pérez de Guzmán el Bueno predoctoral fellowship (A.P.-C.), Agencia Estatal de Investigación SVP-2014-068671 (A.V.), Spanish State Research Agency FPI contract (R.S.), Spanish State Research Agency grant RYC-2015-18056 (J.P.L.-A.), Spanish State Research Agency grant RTI2018-102260-B-100 (J.P.L.-A.), Spanish State Research Agency grant SAF2015-69168-R (V.B.), Spanish State Research Agency grant PGC2018-102172-B-I00 (V.B.), Spanish State Research Agency “Severo Ochoa” Programme for Centers of Excellence in R&D grant SEV-2017-0723 (V.B.), and European Research Council grant 309633 (V.B.).Peer reviewe

Multiple parallel cell lineages in the developing mammalian cerebral cortex

Cortical neurogenesis follows a simple lineage: apical radial glia cells (RGCs) generate basal progenitors, and these produce neurons. How this occurs in species with expanded germinal zones and a folded cortex, such as human, remains unclear. We used single-cell RNA sequencing from individual cortical germinal zones in ferret and barcoded lineage tracking to determine the molecular diversity of progenitor cells and their lineages. We identified multiple RGC classes that initiate parallel lineages, converging onto a common class of newborn neuron. Parallel RGC classes and transcriptomic trajectories were repeated across germinal zones and conserved in ferret and human, but not in mouse. Neurons followed parallel differentiation trajectories in the gyrus and sulcus, with different expressions of human cortical malformation genes. Progenitor cell lineage multiplicity is conserved in the folded mammalian cerebral cortex.This work was supported by ERC-AdG grant Neurocentro-885382 to M.G. and by Spanish State Research Agency grants SAF2015-69168-R, PGC2018-102172-B, and PDI2021-125618NB and “Severo Ochoa” Programme for Centers of Excellence in R&D (CEX-2021-00165-S) to V.B. Additional support was provided by Spanish State Research Agency FPI contract (BES-2016-077737) to L.D.-V.-A., “JdC incorporación” fellowship (IJC2020-044653-I) to V.F., and by Fundación Tatiana Pérez de Guzmán el Bueno fellowship to A.P.-C.With funding from the Spanish government through the "Severo Ochoa Centre of Excellence" accreditation (CEX-2021-00165-S).Peer reviewe

Twitter as a Tool for Teaching and Communicating Microbiology: The #microMOOCSEM Initiative

Online social networks are increasingly used by the population on a daily basis. They are considered a powerful tool for science communication and their potential as educational tools is emerging. However, their usefulness in academic practice is still a matter of debate. Here, we present the results of our pioneering experience teaching a full Basic Microbiology course via Twitter (#microMOOCSEM), consisting of 28 lessons of 40-45 minutes duration each, at a tweet per minute rate during 10 weeks. Lessons were prepared by 30 different lecturers, covering most basic areas in Microbiology and some monographic topics of general interest (malaria, HIV, tuberculosis, etc.). Data analysis on the impact and acceptance of the course were largely affirmative, promoting a 330% enhancement in the followers and a >350-fold increase of the number of visits per month to the Twitter account of the host institution, the Spanish Society for Microbiology. Almost one third of the course followers were located overseas. Our study indicates that Massive Online Open Courses (MOOC) via Twitter are highly dynamic, interactive, and accessible to great audiences, providing a valuable tool for social learning and communicating science. This strategy attracts the interest of students towards particular topics in the field, efficiently complementing customary academic activities, especially in multidisciplinary areas like Microbiology.Versión del edito

MIR3607 regulates cerebral cortex development via activation of Wnt/bCat signaling

Resumen del trabajo presentado al Seminario de Unidad Neurobiología del Desarrollo, celebrado online el 16 de enero de 2020.Peer reviewe

At the intersection between healthy and diseased embryonic development

The size and organization of the brain are determined by the activity of progenitor cells early in development. Key mechanisms regulating progenitor cell biology involve miRNAs. These small noncoding RNA molecules bind mRNAs with high specificity, controlling their abundance and expression. The role of miRNAs in brain development has been studied extensively, but their involvement at early stages remained unknown until recently. Here, recent findings showing the important role of miRNAs in the earliest phases of brain development are reviewed, and it is discussed how loss of specific miRNAs leads to pathological conditions, particularly adult and pediatric brain tumors. Let-7 miRNA downregulation and the initiation of embryonal tumors with multilayered rosettes (ETMR), a novel link recently discovered by the laboratory, are focused upon. Finally, it is discussed how miRNAs may be used for the diagnosis and therapeutic treatment of pediatric brain tumors, with the hope of improving the prognosis of these devastating diseases.A.P. was funded by a predoctoral fellowship from Fundación Tatiana Pérez de Guzmán el Bueno. Work in the lab was supported by grants from the European Research Council (309633) and the Spanish State Research Agency (PGC2018-102172-B-I00, as well as through the “Severo Ochoa” Programme for Centers of Excellence in R&D, ref. SEV-2017-0723).Peer reviewe

Repression of Irs2 by let‐7 miRNAs is essential for homeostasis of the telencephalic neuroepithelium

Structural integrity and cellular homeostasis of the embryonic stem cell niche are critical for normal tissue development. In the telencephalic neuroepithelium, this is controlled in part by cell adhesion molecules and regulators of progenitor cell lineage, but the specific orchestration of these processes remains unknown. Here, we studied the role of microRNAs in the embryonic telencephalon as key regulators of gene expression. By using the early recombiner Rx‐Cre mouse, we identify novel and critical roles of miRNAs in early brain development, demonstrating they are essential to preserve the cellular homeostasis and structural integrity of the telencephalic neuroepithelium. We show that Rx‐Cre;DicerF/F mouse embryos have a severe disruption of the telencephalic apical junction belt, followed by invagination of the ventricular surface and formation of hyperproliferative rosettes. Transcriptome analyses and functional experiments in vivo show that these defects result from upregulation of Irs2 upon loss of let‐7 miRNAs in an apoptosis‐independent manner. Our results reveal an unprecedented relevance of miRNAs in early forebrain development, with potential mechanistic implications in pediatric brain cancer.V.F. was recipient of an FPI fellowship from the Spanish State Research Agency (AEI), and A.P.‐C. was recipient of a predoctoral fellowship from Fundación Tatiana Pérez de Guzmán el Bueno. This work was supported by grants to V.B. from AEI (SAF2015‐69168‐R, PGC2018‐102172‐B‐I00) and European Research Council (309633). V.B. acknowledges financial support from the AEI, through the “Severo Ochoa” Program for Centers of Excellence in R&D (Ref. SEV‐2017‐0723).Peer reviewe

In-hospital and 6-month outcomes in patients with COVID-19 supported with extracorporeal membrane oxygenation (EuroECMO-COVID): a multicentre, prospective observational study

Extracorporeal membrane oxygenation (ECMO) has been widely used in patients with COVID-19, but uncertainty remains about the determinants of in-hospital mortality and data on post-discharge outcomes are scarce. The aims of this study were to investigate the variables associated with in-hospital outcomes in patients who received ECMO during the first wave of COVID-19 and to describe the status of patients 6 months after ECMO initiation