The molecular clock protein Bmal1 regulates cell differentiation in mouse embryonic stem cells
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AuthorGallardo, Amador; Molina, Aldara; Asenjo, Helena G; Martorell Marugán, Jordi; Montes, Rosa; Ramos Mejía, Verónica; Sánchez Pozo, Antonio; Carmona Sáez, Pedro; López Onieva, Lourdes; Landeira, David
Life Science Alliance LLC
Gallardo, A., Molina, A., Asenjo, H. G., Martorell-Marugán, J., Montes, R., Ramos-Mejia, V., ... & Landeira, D. (2020). The molecular clock protein Bmal1 regulates cell differentiation in mouse embryonic stem cells. Life Science Alliance, 3(5). [http://doi.org/10.26508/lsa.201900535]
SponsorshipRamon y Cajal grant of the Spanish ministry of economy and competitiveness RYC2012-10019; Spanish ministry of economy and competitiveness BFU2016-75233-P; Andalusian regional government PC-0246-2017; Fundacion Progreso y Salud (FPS); Instituto de Salud Carlos III European Union (EU) CPII17/00032 PI17/01574; University of Granada
Mammals 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 na¨ıve pluripotent mouse embryonic stem cells (mESCs) to study the role of Bmal1 during early development. We found that, compared to wild-type cells, Bmal12/2 mESCs express higher levels of Nanog protein and altered expression of pluripotencyassociated signalling pathways. Importantly, Bmal12/2 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.