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

Molecular Systems Biology

卷:17

Tian Hong¹  Edwina McGlinn²  Victoria Garside²  Andrew Willems³  Ziyi Liu³  Yi‐Han Lee⁴  Yang‐Zhe Huang⁴  Chung‐Jung Li⁵  Ee Shan Liau⁵  Jun‐An Chen⁵ 

[1] Department of Biochemistry & Cellular and Molecular Biology The University of Tennessee Knoxville TN USA;

[2] EMBL Australia Australian Regenerative Medicine Institute Monash University Clayton Vic Australia;

[3] Genome Science and Technology Program The University of Tennessee Knoxville TN USA;

[4] Institute of Molecular Biology Academia Sinica Taipei Taiwan;

[5] Molecular and Cell Biology Taiwan International Graduate Program Academia Sinica and Graduate Institute of Life Science National Defense Medical Center Taipei Taiwan;

关键词: motor neuron differentiation;    positive feedback loop;    post‐transcriptional regulation;    single‐cell RNA sequencing;    tissue boundary formation;   

DOI  :  10.15252/msb.20209945

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown