Journal Article

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

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

2021

Overview

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. SYNOPSIS 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. Robust lineage segregation of mouse Hoxa5 + and Hoxc8 + motor neurons does not require canonical transcriptional feedback loops. Mathematical modeling derives a wide range of biologically plausible parameters that allow bistability to arise from post‐transcriptional networks. An intuitive interpretation of the mathematical analysis reveals a hidden feedback mechanism involving mRNA‐microRNA interactions. In vitro and in vivo experiments validate the critical roles of two microRNAs in lineage segregation and tissue boundary formation. Graphical Abstract 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.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Animals / Base Sequence / Cell cycle / Cell differentiation / Cell Differentiation - genetics / Cell fate / Cell lineage / Cell Lineage - genetics / Circuits / Differentiation (biology) / EMBO11 / EMBO36 / Embryogenesis / Embryonic growth stage / Feedback / Feedback loops / Feedback, Physiological / Female / Gene Expression Regulation / Gene regulation / Gene Regulatory Networks / Genetics / Homeodomain Proteins - metabolism / Kinetics / Male / Mathematical analysis / Mice / Mice, Inbred C57BL / MicroRNAs / MicroRNAs - genetics / MicroRNAs - metabolism / miRNA / Models, Biological / motor neuron differentiation / Motor Neurons - metabolism / Pattern formation / Positive feedback / positive feedback loop / post‐transcriptional regulation / Proteins / Ribonucleic acid / RNA / RNA, Messenger - genetics / RNA, Messenger - metabolism / RNA-Seq / Robustness (mathematics) / Signal Transduction / Single-Cell Analysis / single‐cell RNA sequencing / Spinal cord / Spinal Cord - cytology / Stem cells / Switches / tissue boundary formation / Transcription / Transcription factors / Transcription Factors - metabolism / Transcription, Genetic / Tretinoin - metabolism