INSERM U861, AFM, Evry Cedex, France.
Development. 2012 Apr;139(7):1247-57. doi: 10.1242/dev.073627. Epub 2012 Feb 22.
The role of microRNAs (miRNAs) as coordinators of stem cell fate has emerged over the last decade. We have used human embryonic stem cells to identify miRNAs involved in neural lineage commitment induced by the inhibition of TGFβ-like molecule-mediated pathways. Among several candidate miRNAs expressed in the fetal brain, the two isoforms of miR-125 alone were detected in a time window compatible with a role in neural commitment in vitro. Functional analysis indicated that miR-125 isoforms were actively involved in the promotion of pluripotent cell conversion into SOX1-positive neural precursors. miR-125 promotes neural conversion by avoiding the persistence of non-differentiated stem cells and repressing alternative fate choices. This was associated with the regulation by miR-125 of SMAD4, a key regulator of pluripotent stem cell lineage commitment. Activation of miR-125 was directly responsive to the levels of TGFβ-like molecules, placing miR-125 at the core of mechanisms that lead to the irreversible neural lineage commitment of pluripotent stem cells in response to external stimuli.
在过去的十年中，miRNAs（微小 RNA）作为干细胞命运的协调者的作用已经显现出来。我们使用人类胚胎干细胞来鉴定在 TGFβ 样分子介导的途径抑制诱导的神经谱系分化中涉及的 miRNAs。在胎儿大脑中表达的几种候选 miRNAs 中，只有 miR-125 的两种同工型在与体外神经分化作用兼容的时间窗口中被检测到。功能分析表明，miR-125 同工型积极参与促进多能细胞转化为 SOX1 阳性神经前体。miR-125 通过避免未分化干细胞的持续存在和抑制替代命运选择来促进神经转化。这与 miR-125 对 SMAD4 的调节有关，SMAD4 是多能干细胞谱系分化的关键调节因子。miR-125 的激活直接响应于 TGFβ 样分子的水平，将 miR-125 置于导致多能干细胞对外部刺激产生不可逆的神经谱系分化的核心机制中。
