MicroRNA governs bistable cell differentiation and lineage segregation via a noncanonical feedback

Chung Jung Li, Ee Shan Liau, Yi Han Lee, Yang Zhe Huang, Ziyi Liu, Andrew Willems, Victoria Garside, Edwina McGlinn, Jun An Chen, Tian Hong

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14 Citations (Scopus)


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.

Original languageEnglish
Article numbere9945
Number of pages22
JournalMolecular Systems Biology
Issue number4
Publication statusPublished - 1 Apr 2021


  • motor neuron differentiation
  • positive feedback loop
  • post-transcriptional regulation
  • single-cell RNA sequencing
  • tissue boundary formation

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