Person:
Torres, Miguel

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Miguel
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Torres
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CNIC
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    Cre recombinase microinjection for single-cell tracing and localised gene targeting.
    (The Company of Biologists, 2023-02-15) Sendra, Miquel; de Dios Hourcade, Juan; Temiño, Susana; Sarabia, Antonio J; Ocaña, Oscar H; Domínguez, Jorge N; Torres, Miguel; Ministerio de Ciencia e Innovación (España); Fundación La Caixa; Unión Europea. Comisión Europea. H2020; Centro Nacional de Investigaciones Cardiovasculares Carlos III (España)
    Tracing and manipulating cells in embryos are essential to understand development. Lipophilic dye microinjections, viral transfection and iontophoresis have been key to map the origin of the progenitor cells that form the different organs in the post-implantation mouse embryo. These techniques require advanced manipulation skills and only iontophoresis, a demanding approach of limited efficiency, has been used for single-cell labelling. Here, we perform lineage tracing and local gene ablation using cell-permeant Cre recombinase (TAT-Cre) microinjection. First, we map the fate of undifferentiated progenitors to the different heart chambers. Then, we achieve single-cell recombination by titrating the dose of TAT-Cre, which allows clonal analysis of nascent mesoderm progenitors. Finally, injecting TAT-Cre to Mycnflox/flox embryos in the primitive heart tube revealed that Mycn plays a cell-autonomous role in maintaining cardiomyocyte proliferation. This tool will help researchers identify the cell progenitors and gene networks involved in organ development, helping to understand the origin of congenital defects.
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    Axial skeleton anterior-posterior patterning is regulated through feedback regulation between Meis transcription factors and retinoic acid.
    (The Company of Biologists, 2021-01-04) López-Delgado, Alejandra C; Delgado, Irene; Cadenas, Vanessa; Sanchez-Cabo, Fatima; Torres, Miguel; Ministerio de Ciencia, Innovación y Universidades (España); Instituto de Salud Carlos III; Comunidad de Madrid (España); Fundación ProCNIC; Ministerio de Economía y Competitividad (España)
    Vertebrate axial skeletal patterning is controlled by co-linear expression of Hox genes and axial level-dependent activity of HOX protein combinations. MEIS transcription factors act as co-factors of HOX proteins and profusely bind to Hox complex DNA; however, their roles in mammalian axial patterning remain unknown. Retinoic acid (RA) is known to regulate axial skeletal element identity through the transcriptional activity of its receptors; however, whether this role is related to MEIS/HOX activity remains unknown. Here, we study the role of Meis in axial skeleton formation and its relationship to the RA pathway in mice. Meis elimination in the paraxial mesoderm produces anterior homeotic transformations and rib mis-patterning associated to alterations of the hypaxial myotome. Although Raldh2 and Meis positively regulate each other, Raldh2 elimination largely recapitulates the defects associated with Meis deficiency, and Meis overexpression rescues the axial skeletal defects in Raldh2 mutants. We propose a Meis-RA-positive feedback loop, the output of which is Meis levels, that is essential to establish anterior-posterior identities and patterning of the vertebrate axial skeleton.
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    Spatial enhancer activation influences inhibitory neuron identity during mouse embryonic development.
    (Nature Publishing Group, 2024-05) Dvoretskova, Elena; Ho, May C; Kittke, Volker; Neuhaus, Florian; Vitali, Ilaria; Lam, Daniel D; Delgado, Irene; Feng, Chao; Torres, Miguel; Winkelmann, Juliane; Mayer, Christian; Unión Europea. Comisión Europea. European Research Council (ERC); Unión Europea. Comisión Europea. H2020
    The mammalian telencephalon contains distinct GABAergic projection neuron and interneuron types, originating in the germinal zone of the embryonic basal ganglia. How genetic information in the germinal zone determines cell types is unclear. Here we use a combination of in vivo CRISPR perturbation, lineage tracing and ChIP-sequencing analyses and show that the transcription factor MEIS2 favors the development of projection neurons by binding enhancer regions in projection-neuron-specific genes during mouse embryonic development. MEIS2 requires the presence of the homeodomain transcription factor DLX5 to direct its functional activity toward the appropriate binding sites. In interneuron precursors, the transcription factor LHX6 represses the MEIS2-DLX5-dependent activation of projection-neuron-specific enhancers. Mutations of Meis2 result in decreased activation of regulatory enhancers, affecting GABAergic differentiation. We propose a differential binding model where the binding of transcription factors at cis-regulatory elements determines differential gene expression programs regulating cell fate specification in the mouse ganglionic eminence.
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    Growth and Morphogenesis during Early Heart Development in Amniotes
    (Multidisciplinary Digital Publishing Institute (MDPI), 2017-11-22) Ivanovitch, Kenzo; Esteban, Isaac; Torres, Miguel; Ministerio de Economía, Industria y Competitividad (España); Instituto de Salud Carlos III; European Molecular Biology Organization; International Human Frontier Science Program Organization; Fundación ProCNIC
    In this review, we will focus on the growth and morphogenesis of the developing heart, an aspect of cardiovascular development to which Antoon Moorman and colleagues have extensively contributed. Over the last decades, genetic studies and characterization of regionally regulated gene programs have provided abundant novel insights into heart development essential to understand the basis of congenital heart disease. Heart morphogenesis, however, is inherently a complex and dynamic three-dimensional process and we are far from understanding its cellular basis. Here, we discuss recent advances in studying heart morphogenesis and regionalization under the light of the pioneering work of Moorman and colleagues, which allowed the reinterpretation of regional gene expression patterns under a new morphogenetic framework. Two aspects of early heart formation will be discussed in particular: (1) the initial formation of the heart tube and (2) the formation of the cardiac chambers by the ballooning process. Finally, we emphasize that in addition to analyses based on fixed samples, new approaches including clonal analysis, single-cell sequencing, live-imaging and quantitative analysis of the data generated will likely lead to novel insights in understanding early heart tube regionalization and morphogenesis in the near future.
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    Pluripotency Surveillance by Myc-Driven Competitive Elimination of Differentiating Cells.
    (Elsevier, 2017-09-25) Díaz-Díaz, Covadonga; Fernandez de Manuel, Laura; Jimenez-Carretero, Daniel; Montoya, María Concepción; Clavería, Cristina; Torres, Miguel; Ministerio de Economía, Industria y Competitividad (España); Comunidad de Madrid (España); Ministerio de Educación, Cultura y Deporte (España); Fundación ProCNIC; Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)
    The mammalian epiblast is formed by pluripotent cells able to differentiate into all tissues of the new individual. In their progression to differentiation, epiblast cells and their in vitro counterparts, embryonic stem cells (ESCs), transit from naive pluripotency through a differentiation-primed pluripotent state. During these events, epiblast cells and ESCs are prone to death, driven by competition between Myc-high cells (winners) and Myc-low cells (losers). Using live tracking of Myc levels, we show that Myc-high ESCs approach the naive pluripotency state, whereas Myc-low ESCs are closer to the differentiation-primed state. In ESC colonies, naive cells eliminate differentiating cells by cell competition, which is determined by a limitation in the time losers are able to survive persistent contact with winners. In the mouse embryo, cell competition promotes pluripotency maintenance by elimination of primed lineages before gastrulation. The mechanism described here is relevant to mammalian embryo development and induced pluripotency.
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    Control of mouse limb initiation and antero-posterior patterning by Meis transcription factors.
    (Nature Publishing Group, 2021-05-25) Delgado, Irene; Giovinazzo, Giovanna; Temiño, Susana; Gauthier, Yves; Balsalobre, Aurelio; Drouin, Jacques; Torres, Miguel; Ministerio de Ciencia e Innovación (España); Fundación ProCNIC
    Meis1 and Meis2 are homeodomain transcription factors that regulate organogenesis through cooperation with Hox proteins. Elimination of Meis genes after limb induction has shown their role in limb proximo-distal patterning; however, limb development in the complete absence of Meis function has not been studied. Here, we report that Meis1/2 inactivation in the lateral plate mesoderm of mouse embryos leads to limb agenesis. Meis and Tbx factors converge in this function, extensively co-binding with Tbx to genomic sites and co-regulating enhancers of Fgf10, a critical factor in limb initiation. Limbs with three deleted Meis alleles show proximal-specific skeletal hypoplasia and agenesis of posterior skeletal elements. This failure in posterior specification results from an early role of Meis factors in establishing the limb antero-posterior prepattern required for Shh activation. Our results demonstrate roles for Meis transcription factors in early limb development and identify their involvement in previously undescribed interaction networks that regulate organogenesis.
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    Pseudodynamic analysis of heart tube formation in the mouse reveals strong regional variability and early left–right asymmetry
    (Springer, 2022-05-16) Esteban, Isaac; Schmidt, Patrick; Desgrange, Audrey; Raiola, Morena; Temiño, Susana; Meilhac, Sigolène M.; Kobbelt, Leif; Torres, Miguel; Ministerio de Ciencia e Innovación (España); Agencia Estatal de Investigación (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Unión Europea. Comisión Europea. H2020; Comunidad de Madrid (España); Ministerio de Economía y Competitividad (España); German Research Foundation; Institut Pasteur; Fundación ProCNIC; Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)
    Understanding organ morphogenesis requires a precise geometrical description of the tissues involved in the process. The high morphological variability in mammalian embryos hinders the quantitative analysis of organogenesis. In particular, the study of early heart development in mammals remains a challenging problem due to imaging limitations and complexity. Here, we provide a complete morphological description of mammalian heart tube formation based on detailed imaging of a temporally dense collection of mouse embryonic hearts. We develop strategies for morphometric staging and quantification of local morphological variations between specimens. We identify hot spots of regionalized variability and identify Nodal-controlled left–right asymmetry of the inflow tracts as the earliest signs of organ left–right asymmetry in the mammalian embryo. Finally, we generate a three-dimensional+t digital model that allows co-representation of data from different sources and provides a framework for the computer modeling of heart tube formation
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    P53 and BCL-2 family proteins PUMA and NOXA define competitive fitness in pluripotent cell competition.
    (Public Library of Science (PLOS), 2024-03) Valverde-Lopez, Jose A; Li-Bao, Lin; Sierra, Rocío; Santos, Elisa; Giovinazzo, Giovanna; Díaz-Díaz, Covadonga; Torres, Miguel; Ministerio de Ciencia e Innovación (España); Fundación ProCNIC; Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)
    Cell Competition is a process by which neighboring cells compare their fitness. As a result, viable but suboptimal cells are selectively eliminated in the presence of fitter cells. In the early mammalian embryo, epiblast pluripotent cells undergo extensive Cell Competition, which prevents suboptimal cells from contributing to the newly forming organism. While competitive ability is regulated by MYC in the epiblast, the mechanisms that contribute to competitive fitness in this context are largely unknown. Here, we report that P53 and its pro-apoptotic targets PUMA and NOXA regulate apoptosis susceptibility and competitive fitness in pluripotent cells. PUMA is widely expressed specifically in pluripotent cells in vitro and in vivo. We found that P53 regulates MYC levels in pluripotent cells, which connects these two Cell Competition pathways, however, MYC and PUMA/NOXA levels are independently regulated by P53. We propose a model that integrates a bifurcated P53 pathway regulating both MYC and PUMA/NOXA levels and determines competitive fitness.
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    Spanish Cell Therapy Network (TerCel): 15 years of successful collaborative translational research
    (Elsevier, 2020-01) Sánchez-Guijo, Fermín; García-Olmo, Damián; Prósper, Felipe; Martínez, Salvador; Zapata, Agustín; Fernández-Avilés, Francisco; Toledo-Aral, Juan José; Torres, Miguel; Fariñas, Isabel; Badimón, Lina; Labandeira-García, José Luis; García-Sancho, Javier; Moraleda, José M; Instituto de Salud Carlos III
    In the current article we summarize the 15-year experience of the Spanish Cell Therapy Network (TerCel), a successful collaborative public initiative funded by the Spanish government for the support of nationwide translational research in this important area. Thirty-two research groups organized in three programs devoted to cardiovascular, neurodegenerative and immune-inflammatory diseases, respectively, currently form the network. Each program has three working packages focused on basic science, pre-clinical studies and clinical application. TerCel has contributed during this period to boost the translational research in cell therapy in Spain, setting up a network of Good Manufacturing Practice-certified cell manufacturing facilities- and increasing the number of translational research projects, publications, patents and clinical trials of the participating groups, especially those in collaboration. TerCel pays particular attention to the public-private collaboration, which, for instance, has led to the development of the first allogeneic cell therapy product approved by the European Medicines Agency, Darvadstrocel. The current collaborative work is focused on the development of multicenter phase 2 and 3 trials that could translate these therapies to clinical practice for the benefit of patients.
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    Lymphoangiocrine signals promote cardiac growth and repair.
    (Nature Publishing Group, 2020-12) Liu, Xiaolei; De la Cruz, Ester; Gu, Xiaowu; Balint, Laszlo; Oxendine-Burns, Michael; Terrones, Tamara; Ma, Wanshu; Kuo, Hui-Hsuan; Lantz, Connor; Bansal, Trisha; Thorp, Edward; Burridge, Paul; Jakus, Zoltán; Herz, Joachim; Cleaver, Ondine; Torres, Miguel; Oliver, Guillermo; Ministerio de Educación (España); European Molecular Biology Organization; Ministerio de Ciencia e Innovación (España); National Institutes of Health (Estados Unidos)
    Recent studies have suggested that lymphatics help to restore heart function after cardiac injury1-6. Here we report that lymphatics promote cardiac growth, repair and cardioprotection in mice. We show that a lymphoangiocrine signal produced by lymphatic endothelial cells (LECs) controls the proliferation and survival of cardiomyocytes during heart development, improves neonatal cardiac regeneration and is cardioprotective after myocardial infarction. Embryos that lack LECs develop smaller hearts as a consequence of reduced cardiomyocyte proliferation and increased cardiomyocyte apoptosis. Culturing primary mouse cardiomyocytes in LEC-conditioned medium increases cardiomyocyte proliferation and survival, which indicates that LECs produce lymphoangiocrine signals that control cardiomyocyte homeostasis. Characterization of the LEC secretome identified the extracellular protein reelin (RELN) as a key component of this process. Moreover, we report that LEC-specific Reln-null mouse embryos develop smaller hearts, that RELN is required for efficient heart repair and function after neonatal myocardial infarction, and that cardiac delivery of RELN using collagen patches improves heart function in adult mice after myocardial infarction by a cardioprotective effect. These results highlight a lymphoangiocrine role of LECs during cardiac development and injury response, and identify RELN as an important mediator of this function.