Person: Torres, Miguel
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Miguel
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Torres
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CNIC
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Publication 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 EconomÃa, Industria y Competitividad (España); Instituto de Salud Carlos III; European Molecular Biology Organization; International Human Frontier Science Program Organization; Fundación ProCNICIn 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.Publication Pluripotency Surveillance by Myc-Driven Competitive Elimination of Differentiating Cells.(Elsevier, 2017-09-25) DÃaz-DÃaz, Covadonga; Fernandez de Manuel, Laura; Jimenez-Carretero, Daniel; Montoya, MarÃa Concepción; ClaverÃa, Cristina; Torres, Miguel; Ministerio de EconomÃa, 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.Publication Dental Epithelial Stem Cells Express the Developmental Regulator Meis1(Frontiers Media, 2019) Sanz-Navarro, Maria; Delgado, Irene; Torres, Miguel; Mustonen, Tuija; Michon, Frederic; Rice, David P; Minerva Foundation; University of Helsinki (Finlandia); Finlands Akademi (Finlandia)MEIS1 is a key developmental regulator of several organs and participates in stem cell maintenance in different niches. However, despite the murine continuously growing incisor being a well described model for the study of adult stem cells, Meis1 has not been investigated in a dental context. Here, we uncover that Meis1 expression in the tooth is confined to the epithelial compartment. Its expression arises during morphogenesis and becomes restricted to the mouse incisor epithelial stem cell niche, the labial cervical loop. Meis1 is specifically expressed by Sox2+ stem cells, which give rise to all dental epithelial cell lineages. Also, we have found that Meis1 in the incisor is coexpressed with potential binding partner Pbx1 during both embryonic and adult stages. Interestingly, Meis2 is present in different areas of the forming tooth and it is not expressed by dental epithelial stem cells, suggesting different roles for these two largely homologous genes. Additionally, we have established the expression patterns of Meis1 and Meis2 during tongue, hair, salivary gland and palate formation. Finally, analysis of Meis1-null allele mice indicated that, similarly, to SOX2, MEIS1 is not essential for tooth initiation, but might have a role during adult incisor renewal.Publication Meis1: effects on motor phenotypes and the sensorimotor system in mice(The Company of Biologists, 2017) Salminen, Aaro V.; Garrett, Lillian; Schormair, Barbara; Rozman, Jan; Giesert, Florian; Niedermeier, Kristina M.; Becker, Lore; Rathkolb, Birgit; Racz, Ildiko; Klingenspor, Martin; Klopstock, Thomas; Wolf, Eckhard; Zimmer, Andreas; Gailus-Durner, Valerie; Torres, Miguel; Fuchs, Helmut.; Hrabe de Angelis, Martin; Wurst, Wolfgang; Hoelter, Sabine M; Winkelmann, Juliane; Emil Aaltosen Säätiö (Finlandia); Unión Europea. Comisión Europea; Federal Ministry of Education & Research (Alemania); Deutsche Forschungsgemeinschaft (Alemania)MEIS1 encodes a developmental transcription factor and has been linked to restless legs syndrome (RLS) in genome-wide association studies. RLS is a movement disorder leading to severe sleep reduction and has a substantial impact on the quality of life of patients. In genome-wide association studies, MEIS1 has consistently been the gene with the highest effect size and functional studies suggest a disease-relevant downregulation. Therefore, haploinsufficiency of Meis1 could be the system with the most potential for modeling RLS in animals. We used heterozygous Meis1-knockout mice to study the effects of Meis1 haploinsufficiency on mouse behavioral and neurological phenotypes, and to relate the findings to human RLS. We exposed the Meis1-deficient mice to assays of motor, sensorimotor and cognitive ability, and assessed the effect of a dopaminergic receptor 2/3 agonist commonly used in the treatment of RLS. The mutant mice showed a pattern of circadian hyperactivity, which is compatible with human RLS. Moreover, we discovered a replicable prepulse inhibition (PPI) deficit in the Meis1-deficient animals. In addition, these mice were hyposensitive to the PPI-reducing effect of the dopaminergic receptor agonist, highlighting a role of Meis1 in the dopaminergic system. Other reported phenotypes include enhanced social recognition at an older age that was not related to alterations in adult olfactory bulb neurogenesis previously shown to be implicated in this behavior. In conclusion, the Meis1-deficient mice fulfill some of the hallmarks of an RLS animal model, and revealed the role of Meis1 in sensorimotor gating and in the dopaminergic systems modulating it.Publication Regulation of Mother-to-Offspring Transmission of mtDNA Heteroplasmy(Cell Press, 2019-12-03) Latorre-Pellicer, Ana; Lechuga-Vieco, Ana V.; Johnston, Iain G; Hämäläinen, Riikka H; Pellico, Juan; Justo-Mendez, Raquel; Fernandez-Toro, Jose Maria; Claveria, Cristina; Guaras, Adela; Sierra, Rocio; Llop, Jordi; Torres, Miguel; Criado-Rodriguez, Luis M.; Suomalainen, Anu; Jones, Nick S; Ruiz-Cabello, Jesus; Enriquez, Jose Antonio; Ministerio de Ciencia, Innovación y Universidades (España); Instituto de Salud Carlos III; Fundación ProCNIC; Centro de Investigación Biomedica en Red - CIBER; Unión Europea. Comisión EuropeamtDNA is present in multiple copies in each cell derived from the expansions of those in the oocyte. Heteroplasmy, more than one mtDNA variant, may be generated by mutagenesis, paternal mtDNA leakage, and novel medical technologies aiming to prevent inheritance of mtDNA-linked diseases. Heteroplasmy phenotypic impact remains poorly understood. Mouse studies led to contradictory models of random drift or haplotype selection for mother-to-offspring transmission of mtDNA heteroplasmy. Here, we show that mtDNA heteroplasmy affects embryo metabolism, cell fitness, and induced pluripotent stem cell (iPSC) generation. Thus, genetic and pharmacological interventions affecting oxidative phosphorylation (OXPHOS) modify competition among mtDNA haplotypes during oocyte development and/or at early embryonic stages. We show that heteroplasmy behavior can fall on a spectrum from random drift to strong selection, depending on mito-nuclear interactions and metabolic factors. Understanding heteroplasmy dynamics and its mechanisms provide novel knowledge of a fundamental biological process and enhance our ability to mitigate risks in clinical applications affecting mtDNA transmission.Publication ChIP-Seq and RNA-Seq Analyses Identify Components of the Wnt and Fgf Signaling Pathways as Prep1 Target Genes in Mouse Embryonic Stem Cells(Public Library of Science (PLOS), 2015) Laurent, Audrey; Calabrese, Manuela; Warnatz, Hans-Joerg; Yaspo, Marie-Laure; Tkachuk, Vsevolod; Torres, Miguel; Blasi, Francesco; Penkov, Dmitry; Fondazione Umberto Veronesi; Italian Association for Cancer Research; Fondazione Cariplo; Ministero della Salute (Italia); Max Planck Society; Unión Europea. Comisión Europea; Ministerio de EconomÃa y Competitividad (España); Russian Foundation for Basic ResearchThe Prep1 (Pknox1) homeodomain transcription factor is essential at multiple stages of embryo development. In the E11.5 embryo trunk, we previously estimated that Prep1 binds about 3,300 genomic sites at a highly specific decameric consensus sequence, mainly governing basal cellular functions. We now show that in embryonic stem (ES) cells Prep1 binding pattern only partly overlaps that of the embryo trunk, with about 2,000 novel sites. Moreover, in ES cells Prep1 still binds mostly to promoters, as in total embryo trunk but, among the peaks bound exclusively in ES cells, the percentage of enhancers was threefold higher. RNA-seq identifies about 1800 genes down-regulated in Prep1(-/-) ES cells which belong to gene ontology categories not enriched in the E11.5 Prep1(i/i) differentiated embryo, including in particular essential components of the Wnt and Fgf pathways. These data agree with aberrant Wnt and Fgf expression levels in the Prep1(-/-) ES cells with a deficient embryoid bodies (EBs) formation and differentiation. Re-establishment of the Prep1 level rescues the phenotype.Publication Exercise triggers ARVC phenotype in mice expressing a disease-causing mutated version of human plakophilin-2.(Elsevier, 2015-04-14) Cruz, Francisco M; Sanz-Rosa, David; Roche-Molina, Marta; GarcÃa-Prieto, Jaime; GarcÃa-Ruiz, José M; Pizarro, Gonzalo; Jiménez-Borreguero, Luis J; Torres, Miguel; Bernad, Antonio; RuÃz-Cabello, Jesús; Fuster, ValentÃn; Ibáñez, Borja; Bernal, Juan ABACKGROUND Exercise has been proposed as a trigger for arrhythmogenic right ventricular cardiomyopathy (ARVC) phenotype manifestation; however, research is hampered by the limited availability of animal models in which disease-associated mutations can be tested. OBJECTIVES This study evaluated the impact of exercise on ARVC cardiac manifestations in mice after adeno-associated virus (AAV)-mediated gene delivery of mutant human PKP2, which encodes the desmosomal protein plakophilin-2. METHODS We developed a new model of cardiac tissue-specific transgenic-like mice on the basis of AAV gene transfer to test the potential of a combination of a human PKP2 mutation and endurance training to trigger an ARVC-like phenotype. RESULTS Stable cardiac expression of mutant PKP2 (c.2203C>T), encoding the R735X mutant protein, was achieved 4 weeks after a single AAV9-R735X intravenous injection. High-field cardiac magnetic resonance over a 10-month postinfection follow-up did not detect an overt right ventricular (RV) phenotype in nonexercised (sedentary) mice. In contrast, endurance exercise training (initiated 2 weeks after AAV9-R735X injection) resulted in clear RV dysfunction that resembled the ARVC phenotype (impaired global RV systolic function and RV regional wall motion abnormalities on cardiac magnetic resonance). At the histological level, RV samples from endurance-trained R735X-infected mice displayed connexin 43 delocalization at intercardiomyocyte gap junctions, a change not observed in sedentary mice. CONCLUSIONS The introduction of the PKP2 R735X mutation into mice resulted in an exercise-dependent ARVC phenotype. The R735X mutation appears to function as a dominant-negative variant. This novel system for AAV-mediated introduction of a mutation into wild-type mice has broad potential for study of the implication of diverse mutations in complex cardiomyopathies.Publication Gadd45g is essential for primary sex determination, male fertility and testis development(Public Library of Science (PLOS), 2013) Johnen, Heiko; González-Silva, Laura; Carramolino, Laura; Flores, Juana Maria; Torres, Miguel; Salvador, Jesús M; Unión Europea. Comisión Europea; Unión Europea. Comisión Europea. European Research Council (ERC); Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (España)In humans and most mammals, differentiation of the embryonic gonad into ovaries or testes is controlled by the Y-linked gene SRY. Here we show a role for the Gadd45g protein in this primary sex differentiation. We characterized mice deficient in Gadd45a, Gadd45b and Gadd45g, as well as double-knockout mice for Gadd45ab, Gadd45ag and Gadd45bg, and found a specific role for Gadd45g in male fertility and testis development. Gadd45g-deficient XY mice on a mixed 129/C57BL/6 background showed varying degrees of disorders of sexual development (DSD), ranging from male infertility to an intersex phenotype or complete gonadal dysgenesis (CGD). On a pure C57BL/6 (B6) background, all Gadd45g(-/-) XY mice were born as completely sex-reversed XY-females, whereas lack of Gadd45a and/or Gadd45b did not affect primary sex determination or testis development. Gadd45g expression was similar in female and male embryonic gonads, and peaked around the time of sex differentiation at 11.5 days post-coitum (dpc). The molecular cause of the sex reversal was the failure of Gadd45g(-/-) XY gonads to achieve the SRY expression threshold necessary for testes differentiation, resulting in ovary and Müllerian duct development. These results identify Gadd45g as a candidate gene for male infertility and 46,XY sex reversal in humans.Publication A predictive model of asymmetric morphogenesis from 3D reconstructions of mouse heart looping dynamics(eLife Sciences Publications, 2017) Le Garrec, Jean-François; DomÃnguez, Jorge N; Desgrange, Audrey; Ivanovitch, Kenzo; Raphaël, Etienne; Bangham, J Andrew; Torres, Miguel; Coen, Enrico; Mohun, Timothy J; Meilhac, Sigolène M; Agence Nationale de la Recherche (Francia); Institut National de la Santé et de la Recherche Médicale (Francia); Institut Pasteur; Ministerio de EconomÃa, Industria y Competitividad (España)How left-right patterning drives asymmetric morphogenesis is unclear. Here, we have quantified shape changes during mouse heart looping, from 3D reconstructions by HREM. In combination with cell labelling and computer simulations, we propose a novel model of heart looping. Buckling, when the cardiac tube grows between fixed poles, is modulated by the progressive breakdown of the dorsal mesocardium. We have identified sequential left-right asymmetries at the poles, which bias the buckling in opposite directions, thus leading to a helical shape. Our predictive model is useful to explore the parameter space generating shape variations. The role of the dorsal mesocardium was validated in Shh-/- mutants, which recapitulate heart shape changes expected from a persistent dorsal mesocardium. Our computer and quantitative tools provide novel insight into the mechanism of heart looping and the contribution of different factors, beyond the simple description of looping direction. This is relevant to congenital heart defects.Publication Live imaging of heart tube development in mouse reveals alternating phases of cardiac differentiation and morphogenesis(2017) Ivanovitch, Kenzo; Termino, Susana; Torres, Miguel; Ministerio de EconomÃa y Competitividad (España); Instituto de Salud Carlos III; European Molecular Biology Organization; International Human Frontier Science Program OrganizationDuring vertebrate heart development, two progenitor populations, first and second heart fields (FHF, SHF), sequentially contribute to longitudinal subdivisions of the heart tube (HT), with the FHF contributing the left ventricle and part of the atria, and the SHF the rest of the heart. Here, we study the dynamics of cardiac differentiation and morphogenesis by tracking individual cells in live analysis of mouse embryos. We report that during an initial phase, FHF precursors differentiate rapidly to form a cardiac crescent, while limited morphogenesis takes place. In a second phase, no differentiation occurs while extensive morphogenesis, including splanchnic mesoderm sliding over the endoderm, results in HT formation. In a third phase, cardiac precursor differentiation resumes and contributes to SHF-derived regions and the dorsal closure of the HT. These results reveal tissue-level coordination between morphogenesis and differentiation during HT formation and provide a new framework to understand heart development.