Gallardo, AmadorMolina, AldaraAsenjo, Helena G.Martorell-Marugán, JordiMontes, RosaRamos-Mejia, VerónicaSanchez-Pozo, AntonioCarmona-Sáez, PedroLopez-Onieva, LourdesLandeira, David2022-03-282022-03-282020-04-13Gallardo A, Molina A, Asenjo HG, Martorell-Marugán J, Montes R, Ramos-Mejia V, et al. The molecular clock protein Bmal1 regulates cell differentiation in mouse embryonic stem cells. Life Sci Alliance. 2020 Apr 13;3(5):e201900535.http://hdl.handle.net/10668/3495Mammals optimize their physiology to the light-dark cycle by synchronization of the master circadian clock in the brain with peripheral clocks in the rest of the tissues of the body. Circadian oscillations rely on a negative feedback loop exerted by the molecular clock that is composed by transcriptional activators Bmal1 and Clock, and their negative regulators Period and Cryptochrome. Components of the molecular clock are expressed during early development, but onset of robust circadian oscillations is only detected later during embryogenesis. Here, we have used naïve pluripotent mouse embryonic stem cells (mESCs) to study the role of Bmal1 during early development. We found that, compared to wild-type cells, Bmal1-/- mESCs express higher levels of Nanog protein and altered expression of pluripotency-associated signalling pathways. Importantly, Bmal1-/- mESCs display deficient multi-lineage cell differentiation capacity during the formation of teratomas and gastrula-like organoids. Overall, we reveal that Bmal1 regulates pluripotent cell differentiation and propose that the molecular clock is an hitherto unrecognized regulator of mammalian development.enAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/ARNTL transcription factorsClock proteinsCircadian clocksCryptochromesGene expressionPluripotent stem cellsFactores de transcripción ARNTLProteínas clockRelojes circadianosCriptocromosExpresión genéticaCélulas madre pluripotentesMiceRatonesMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Circadian Rhythm Signaling Peptides and Proteins::ARNTL Transcription FactorsMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Circadian Rhythm Signaling Peptides and Proteins::CLOCK ProteinsMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell DifferentiationMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::Chronobiology Phenomena::Periodicity::Biological Clocks::Circadian ClocksMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::Chronobiology Phenomena::Periodicity::Circadian RhythmMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::Physiological Processes::Homeostasis::Feedback, PhysiologicalMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene ExpressionMedical Subject Headings::Anatomy::Cells::Stem Cells::Pluripotent Stem Cells::Induced Pluripotent Stem CellsMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Circadian Rhythm Signaling Peptides and Proteins::Period Circadian ProteinsMedical Subject Headings::Anatomy::Cells::Stem Cells::Pluripotent Stem CellsMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression::Transcription, Geneticresearch article32284355open access10.26508/lsa.2019005352575-1077PMC7156284