MicroRNA Governs Bistable Cell Differentiation and Lineage Segregation Via a Noncanonical Feedback

Overview

Journal Mol Syst Biol

Specialty Molecular Biology

Date 2021 Apr 23

PMID 33890404

Citations 21

Authors

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

Affiliations

Soon will be listed here.

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.

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