MicroRNA governs bistable cell differentiation and lineage segregation via a noncanonical feedback. Issue 4 (23rd April 2021)

• Record Type: Journal Article
• Authors: Li, Chung‐Jung; Liau, Ee Shan; Lee, Yi‐Han; Huang, Yang‐Zhe; Liu, Ziyi; Willems, Andrew; Garside, Victoria; McGlinn, Edwina; Chen, Jun‐An; Hong, Tian
• Is Part Of: Molecular systems biology. Volume 17:Issue 4(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-04-23
• Subjects: motor neuron differentiation -- positive feedback loop -- post‐transcriptional regulation -- single‐cell RNA sequencing -- tissue boundary formation; Molecular biology -- Periodicals; Systems biology -- Periodicals; 572.8
• DOI: 10.15252/msb.20209945
• Languages: English
• ISSNs: 1744-4292

Abstract

Abstract: 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. 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.