Ceinge Biotecnologie Avanzate, Naples, Italy.
FASEB J. 2012 Oct;26(10):3957-68. doi: 10.1096/fj.12-211607. Epub 2012 Jul 2.
Bone morphogenetic protein 4 (BMP4) plays an important role in maintaining embryonic stem cells (ESCs) in the undifferentiated state and in the regulation of lineage commitment. We recently identified a transmembrane protein, named Dies1, the suppression of which by RNA interference blocks mouse ESC differentiation by interfering with the BMP4 signaling. We asked whether modulation of Dies1 levels could be a physiological mechanism to regulate ESC pluripotency and/or differentiation. We demonstrated that miR-125a targets Dies1 and regulates its expression in ESCs. The overexpression of miR-125a impairs differentiation, and this effect is specifically mediated by Dies1 down-regulation and accompanied by a decrease of BMP4 signaling. We also found that Dies1 is associated with BMP4 receptor complex and that BMP4 activates the transcription of miR-125a gene. Therefore, a feedback loop exists that sets ESC sensitivity to BMP4. The analysis of this regulatory mechanism revealed that miR-125a overexpression and the consequent inhibition of the BMP4 signaling arrest the cells in the epiblast stem cell (epiSC) status, due to the concomitant activation of the Nodal/Activin pathway.
骨形态发生蛋白 4（BMP4）在维持胚胎干细胞（ESCs）未分化状态和调节谱系分化中起着重要作用。我们最近鉴定出一种跨膜蛋白，称为 Dies1，其通过 RNA 干扰抑制可通过干扰 BMP4 信号通路阻断小鼠 ESC 分化。我们想知道 Dies1 水平的调节是否可以成为调节 ESC 多能性和/或分化的生理机制。我们证明 miR-125a 靶向 Dies1 并调节其在 ESCs 中的表达。miR-125a 的过表达会损害分化，这种作用是通过 Dies1 的下调特异性介导的，并且伴随着 BMP4 信号的减少。我们还发现 Dies1 与 BMP4 受体复合物相关，并且 BMP4 激活 miR-125a 基因的转录。因此，存在一个反馈回路，使 ESC 对 BMP4 的敏感性。对该调节机制的分析表明，miR-125a 的过表达和随之而来的 BMP4 信号抑制由于 Nodal/Activin 途径的同时激活，将细胞阻滞在胚外干细胞（epiSC）状态。
