Person: Torres, Miguel
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First Name
Miguel
Last Name
Torres
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CNIC
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Publication 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 ProCNICMeis1 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.Publication 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.Publication Proximo-distal positional information encoded by an Fgf-regulated gradient of homeodomain transcription factors in the vertebrate limb.(American Association for the Advancement of Science (AAAS), 2020-06) Delgado, Irene; López-Delgado, Alejandra C; Roselló-Díez, Alberto; Giovinazzo, Giovanna; Cadenas, Vanessa; Fernandez-de-Manuel, Laura; Sanchez-Cabo, Fatima; Anderson, Matthew J; Lewandoski, Mark; Torres, Miguel; Ministerio de Ciencia, Innovación y Universidades (España); Instituto de Salud Carlos III; Comunidad de Madrid (España); Fundación ProCNICThe positional information theory proposes that a coordinate system provides information to embryonic cells about their position and orientation along a patterning axis. Cells interpret this information to produce the appropriate pattern. During development, morphogens and interpreter transcription factors provide this information. We report a gradient of Meis homeodomain transcription factors along the mouse limb bud proximo-distal (PD) axis antiparallel to and shaped by the inhibitory action of distal fibroblast growth factor (FGF). Elimination of Meis results in premature limb distalization and HoxA expression, proximalization of PD segmental borders, and phocomelia. Our results show that Meis transcription factors interpret FGF signaling to convey positional information along the limb bud PD axis. These findings establish a new model for the generation of PD identities in the vertebrate limb and provide a molecular basis for the interpretation of FGF signal gradients during axial patterning.Publication Regulation of Myc transcription by an enhancer cluster dedicated to pluripotency and early embryonic expression.(Nature Publishing Group, 2024-05-10) Li-Bao, Lin; Díaz-Díaz, Covadonga; Raiola, Morena; Sierra, Rocío; Temiño, Susana; Moya, Francisco J; Rodriguez-Perales, Sandra; Santos, Elisa; Giovinazzo, Giovanna; Bleckwehl, Tore; Rada-Iglesias, Álvaro; Spitz, Francois; Torres, Miguel; Agencia Estatal de Investigación (España); Unión Europea. Comisión Europea; Comunidad de Madrid (España); Instituto de Salud Carlos III; Ministerio de Ciencia, Innovación y Universidades (España); Fundación ProCNIC; Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)MYC plays various roles in pluripotent stem cells, including the promotion of somatic cell reprogramming to pluripotency, the regulation of cell competition and the control of embryonic diapause. However, how Myc expression is regulated in this context remains unknown. The Myc gene lies within a ~ 3-megabase gene desert with multiple cis-regulatory elements. Here we use genomic rearrangements, transgenesis and targeted mutation to analyse Myc regulation in early mouse embryos and pluripotent stem cells. We identify a topologically-associated region that homes enhancers dedicated to Myc transcriptional regulation in stem cells of the pre-implantation and early post-implantation embryo. Within this region, we identify elements exclusively dedicated to Myc regulation in pluripotent cells, with distinct enhancers that sequentially activate during naive and formative pluripotency. Deletion of pluripotency-specific enhancers dampens embryonic stem cell competitive ability. These results identify a topologically defined enhancer cluster dedicated to early embryonic expression and uncover a modular mechanism for the regulation of Myc expression in different states of pluripotency.