TY - JOUR
T1 - MicroRNA governs bistable cell differentiation and lineage segregation via a noncanonical feedback
AU - Li, Chung Jung
AU - Liau, Ee Shan
AU - Lee, Yi Han
AU - Huang, Yang Zhe
AU - Liu, Ziyi
AU - Willems, Andrew
AU - Garside, Victoria
AU - McGlinn, Edwina
AU - Chen, Jun An
AU - Hong, Tian
N1 - Funding Information:
We thank the Genomic, FACS, and Imaging cores of IMB, Academia Sinica, for considerable technical help. The Hoxc8‐IRES‐Cre line was a kind gift from Prof. Mario Capecchi from the School of Medicine, University of Utah. The miR‐23–27~24 DKO mouse founder strains were generated by the Transgenics Core Facility of IMB. We thank J. Dasen (NYU) for the gift of Hoxa5 antibody and H. Wichterle (Columbia University) for giving us Hb9 antibody and Hb9::GFP ESCs. We also acknowledge Y.‐H. Su and S.‐J. Chou (ICOB, Academia Sinica) for discussions on our experimental results, members of the JAC laboratory members for proofreading, Mien Chang for mouse strain maintenance, and J O'Brien for further reviewing the manuscript. We thank X. Cheng and D. Handwerk for helpful discussions and suggestions. This work was supported by the HHS|NIH|National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health under Award Number R01GM140462 to T.H. This work was supported by Academia Sinica (CDA‐107‐L05 & AS‐GC‐109‐03), Ministry of Science and Technology, Taiwan (MOST) (109‐2314‐B‐001‐010‐MY3), and National Health Research Institutes (NHRI) (NHRI‐EX110‐10831NI).
Funding Information:
We thank the Genomic, FACS, and Imaging cores of IMB, Academia Sinica, for considerable technical help. The Hoxc8-IRES-Cre line was a kind gift from Prof. Mario Capecchi from the School of Medicine, University of Utah. The miR-23?27~24 DKO mouse founder strains were generated by the Transgenics Core Facility of IMB. We thank J. Dasen (NYU) for the gift of Hoxa5 antibody and H. Wichterle (Columbia University) for giving us Hb9 antibody and Hb9::GFP ESCs. We also acknowledge Y.-H. Su and S.-J. Chou (ICOB, Academia Sinica) for discussions on our experimental results, members of the JAC laboratory members for proofreading, Mien Chang for mouse strain maintenance, and J O'Brien for further reviewing the manuscript. We thank X. Cheng and D. Handwerk for helpful discussions and suggestions. This work was supported by the HHS|NIH|National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health under Award Number R01GM140462 to T.H. This work was supported by Academia Sinica (CDA-107-L05 & AS-GC-109-03), Ministry of Science and Technology, Taiwan (MOST) (109-2314-B-001-010-MY3), and National Health Research Institutes (NHRI) (NHRI-EX110-10831NI).
Publisher Copyright:
© 2021 The Authors. Published under the terms of the CC BY 1.0 license
PY - 2021/4/1
Y1 - 2021/4/1
N2 - 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.
AB - 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.
KW - motor neuron differentiation
KW - positive feedback loop
KW - post-transcriptional regulation
KW - single-cell RNA sequencing
KW - tissue boundary formation
UR - http://www.scopus.com/inward/record.url?scp=85104961728&partnerID=8YFLogxK
U2 - 10.15252/msb.20209945
DO - 10.15252/msb.20209945
M3 - Article
C2 - 33890404
AN - SCOPUS:85104961728
VL - 17
JO - Molecular Systems Biology
JF - Molecular Systems Biology
SN - 1744-4292
IS - 4
M1 - e9945
ER -