MicroRNA governs bistable cell differentiation and lineage segregation via a noncanonical feedback.
MicroRNA governs bistable cell differentiation and lineage segregation via a noncanonical feedback.
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DOI：
10.15252/msb.20209945
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发表时间：
2021-04
影响因子：
9.9
通讯作者：
Hong T
中科院分区：
文献类型：
--
作者：
Li CJ;Liau ES;Lee YH;Huang YZ;Liu Z;Willems A;Garside V;McGlinn E;Chen JA;Hong T
由转录调控驱动的正反馈一直被认为是胚胎发生过程中细胞谱系分离的关键机制。使用发育中的脊髓作为范例，我们发现，典型的，转录驱动的反馈不能解释由两个主要因素Hoxa 5和Hoxc 8标记的运动神经元亚型的鲁棒谱系分离。我们提出了一种涉及基本microRNA-mRNA反应回路的反馈机制，该反应回路不同于已知的反馈环样结构。令人惊讶的是，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正反馈开关，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。使用胚胎干细胞分化和小鼠遗传学，我们证实microRNA-mRNA电路支配组织边界和运动神经元分化滞后相对于瞬时形态信号。我们的研究结果揭示了一种以前未被充分认识的反馈机制，这种机制可能在细胞命运决定和组织模式中具有广泛的功能。稳健的细胞命运决定和精确的组织边界形成对于发育至关重要。这项研究报告了小鼠脊髓发育中细胞谱系分离过程中涉及mRNA-microRNA相互作用的反馈机制。
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. Robust cell fate decision and precise tissue boundary formation are critical for development. This study reports a feedback mechanism involving mRNA‐microRNA interactions during cell lineage segregation in mouse spinal cord development.
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影响因子：
64.8
作者：
Dasen, JS;Liu, JP;Jessell, TM
通讯作者：
Jessell, TM
影响因子：
9.2
作者：
Baccarini, Alessia;Chauhan, Hemangini;Gardner, Thomas J.;Jayaprakash, Anitha D.;Sachidanandam, Ravi;Brown, Brian D.
通讯作者：
Brown, Brian D.
影响因子：
64.5
作者：
Dasen, JS;Tice, BC;Jessell, TM
通讯作者：
Jessell, TM
DOI：
10.1126/science.1215691
发表时间：
2012-04-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Djuranovic S;Nahvi A;Green R
通讯作者：
Green R
影响因子：
7.7
作者：
de la Mata, Manuel;Gaidatzis, Dimos;Grosshans, Helge
通讯作者：
Grosshans, Helge