Centre for Genomics and Oncological Research (GENYO), Granada, Spain.
Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain.
Life Sci Alliance. 2020 Apr 13;3(5). doi: 10.26508/lsa.201900535. Print 2020 May.
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 naïve pluripotent mouse embryonic stem cells (mESCs) to study the role of Bmal1 during early development. We found that, compared to wild-type cells, -/- mESCs express higher levels of Nanog protein and altered expression of pluripotency-associated signalling pathways. Importantly, 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.
哺乳动物通过将大脑中的主生物钟与身体其他组织中的外周时钟同步，使其生理机能适应昼夜节律。昼夜节律波动依赖于分子钟施加的负反馈环，该分子钟由转录激活因子 Bmal1 和 Clock 及其负调节剂 Period 和 Cryptochrome 组成。分子钟的组成部分在早期发育过程中表达，但在胚胎发生过程中稍后才检测到稳健的昼夜节律波动的开始。在这里，我们使用幼稚的多能性小鼠胚胎干细胞 (mESC) 来研究 Bmal1 在早期发育中的作用。我们发现，与野生型细胞相比，-/- mESC 表达更高水平的 Nanog 蛋白和改变的多能性相关信号通路表达。重要的是，-/- mESC 在形成畸胎瘤和类囊胚体类器官时表现出缺陷的多能细胞分化能力。总的来说，我们揭示了 Bmal1 调节多能细胞分化，并提出分子钟是哺乳动物发育的一个迄今为止尚未被认识的调节因子。
