Departments of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15804-9. doi: 10.1073/pnas.0915022107. Epub 2010 Aug 18.
When stem cells and multipotent progenitors differentiate, they undergo fate restriction, enabling a single fate and blocking differentiation along alternative routes. We herein present a mechanism whereby such unequivocal commitment is achieved, based on microRNA (miRNA)-dependent repression of an alternative cell fate. We show that the commitment of monocyte RAW264.7 progenitors to active macrophage differentiation involves rapid up-regulation of miR-155 expression, which leads to the suppression of the alternative pathway, namely RANK ligand-induced osteoclastogenesis, by repressing the expression of MITF, a transcription factor essential for osteoclast differentiation. A temporal asymmetry, whereby miR-155 expression precedes and overrides the activation of the osteoclast transcriptional program, provides the means for coherent macrophage differentiation, even in the presence of osteoclastogenic signals. Based on these findings, we propose that miRNA may provide a general mechanism for the unequivocal commitment underlying stem cell differentiation.
当干细胞和多能祖细胞分化时，它们会经历命运限制，从而实现单一命运，并阻止沿着替代途径进行分化。本文提出了一种基于 microRNA（miRNA）依赖性抑制替代细胞命运的机制，该机制可实现这种明确的命运决定。我们表明，单核细胞 RAW264.7 祖细胞向活性巨噬细胞分化的分化涉及 miR-155 表达的快速上调，这导致通过抑制 MITF 的表达来抑制替代途径，即 RANK 配体诱导的破骨细胞发生，MITF 是破骨细胞分化所必需的转录因子。时间不对称性，即 miR-155 表达先于并超过破骨细胞转录程序的激活，为一致的巨噬细胞分化提供了手段，即使存在破骨细胞发生信号也是如此。基于这些发现，我们提出 miRNA 可能为干细胞分化所依据的明确的命运决定提供了一种普遍机制。
