{"doi":"10.15252/msb.20209945","title":"MicroRNA governs bistable cell differentiation and lineage segregation via a noncanonical feedback","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.","journal":"Molecular Systems Biology","year":2021,"id":165722,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":35,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9468,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":689582,"name":"Ee Shan Liau","orcid":"0000-0002-4115-5573","position":1,"is_corresponding":false},{"id":689583,"name":"Yi‐Han Lee","orcid":"0000-0001-7650-2443","position":2,"is_corresponding":false},{"id":689584,"name":"Yang‐Zhe Huang","orcid":"0000-0002-3875-994X","position":3,"is_corresponding":false},{"id":379164,"name":"Ziyi Liu","orcid":"0000-0001-7242-2227","position":4,"is_corresponding":false},{"id":105036,"name":"Andrew Willems","orcid":"0000-0002-7927-0745","position":5,"is_corresponding":false},{"id":689585,"name":"Victoria C. Garside","orcid":"0000-0002-4646-0964","position":6,"is_corresponding":false},{"id":689586,"name":"Edwina McGlinn","orcid":"0000-0002-1829-986X","position":7,"is_corresponding":false},{"id":689587,"name":"Jun‐An Chen","orcid":"0000-0001-9870-3203","position":8,"is_corresponding":false},{"id":379166,"name":"Tian Hong","orcid":"0000-0002-8212-7050","position":9,"is_corresponding":false},{"id":689581,"name":"Chung-Jung Li","orcid":"0000-0002-4114-3628","position":0,"is_corresponding":true}],"reference_count":81,"raw_metadata":null,"created_at":"2026-07-18T23:45:40.838485Z","pmid":"33890404","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}