Department of Cell Biology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Department of Molecular Biology, Faculty of Science, Radboud University, Radboud Institute for Molecular Life Sciences (RIMLS), Nijmegen, The Netherlands.
Nat Cell Biol. 2020 May;22(5):534-545. doi: 10.1038/s41556-020-0508-x. Epub 2020 May 4.
Following implantation, the naive pluripotent epiblast of the mouse blastocyst generates a rosette, undergoes lumenogenesis and forms the primed pluripotent egg cylinder, which is able to generate the embryonic tissues. How pluripotency progression and morphogenesis are linked and whether intermediate pluripotent states exist remain controversial. We identify here a rosette pluripotent state defined by the co-expression of naive factors with the transcription factor OTX2. Downregulation of blastocyst WNT signals drives the transition into rosette pluripotency by inducing OTX2. The rosette then activates MEK signals that induce lumenogenesis and drive progression to primed pluripotency. Consequently, combined WNT and MEK inhibition supports rosette-like stem cells, a self-renewing naive-primed intermediate. Rosette-like stem cells erase constitutive heterochromatin marks and display a primed chromatin landscape, with bivalently marked primed pluripotency genes. Nonetheless, WNT induces reversion to naive pluripotency. The rosette is therefore a reversible pluripotent intermediate whereby control over both pluripotency progression and morphogenesis pivots from WNT to MEK signals.
胚胎植入后，小鼠囊胚的原始多能上胚层会生成一个玫瑰花结，经历腔形成并形成初始多潜能的卵圆柱，它能够产生胚胎组织。多能性进展和形态发生如何联系，以及是否存在中间多能状态仍然存在争议。我们在这里鉴定了一种玫瑰花结多能性状态，其特征是幼稚因子与转录因子 OTX2 的共表达。下调囊胚 WNT 信号通过诱导 OTX2 驱动向玫瑰花结多能性的转变。然后，玫瑰花结激活 MEK 信号，诱导腔形成并驱动向初始多潜能性的进展。因此，联合 WNT 和 MEK 抑制支持玫瑰花结样干细胞，这是一种自我更新的原始-初始中间状态。玫瑰花结样干细胞消除组成型异染色质标记，并显示出初始染色质景观，具有双价标记的初始多潜能基因。尽管如此，WNT 诱导向原始多潜能性的逆转。因此，玫瑰花结是一种可逆的多潜能中间状态，其中多潜能性进展和形态发生的控制从 WNT 到 MEK 信号发生枢轴转换。
