Molecular and Cell Biology, Taiwan International Graduate Program, Academia Sinica and Graduate Institute of Life Science, National Defense Medical Center, Taipei, Taiwan.
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
Mol Syst Biol. 2021 Apr;17(4):e9945. doi: 10.15252/msb.20209945.
Positive feedback driven by transcriptional regulation has long been considered a key mechanism underlying cell lineage segregation during embryogenesis. Using the developing spinal cord as a paradigm, we found that canonical, transcription-driven feedback cannot explain robust lineage segregation of motor neuron subtypes marked by two cardinal factors, Hoxa5 and Hoxc8. We propose a feedback mechanism involving elementary microRNA-mRNA reaction circuits that differ from known feedback loop-like structures. Strikingly, we show that a wide range of biologically plausible post-transcriptional regulatory parameters are sufficient to generate bistable switches, a hallmark of positive feedback. Through mathematical analysis, we explain intuitively the hidden source of this feedback. Using embryonic stem cell differentiation and mouse genetics, we corroborate that microRNA-mRNA circuits govern tissue boundaries and hysteresis upon motor neuron differentiation with respect to transient morphogen signals. Our findings reveal a previously underappreciated feedback mechanism that may have widespread functions in cell fate decisions and tissue patterning.
转录调控驱动的正反馈长期以来一直被认为是胚胎发生过程中细胞谱系分离的关键机制。我们以发育中的脊髓为范例，发现经典的、转录驱动的反馈不能解释由两个主要因子 Hoxa5 和 Hoxc8 标记的运动神经元亚型的强大谱系分离。我们提出了一种涉及基本 microRNA-mRNA 反应回路的反馈机制，该机制不同于已知的反馈环样结构。引人注目的是，我们表明，广泛的生物学上合理的转录后调控参数足以产生双稳态开关，这是正反馈的标志。通过数学分析，我们直观地解释了这种反馈的隐藏来源。通过胚胎干细胞分化和小鼠遗传学，我们证实，microRNA-mRNA 回路在运动神经元分化过程中控制组织边界和对短暂形态发生素信号的滞后，与组织边界和滞后有关。我们的发现揭示了一种以前被低估的反馈机制，它可能在细胞命运决定和组织模式形成中具有广泛的功能。
