title: Synthetic lateral inhibition governs cell-type bifurcation with robust ratios.
abstract: Cell-type diversity in multicellular organisms is created through a series of binary cell fate decisions. Lateral inhibition controlled by Delta-Notch signalling is the core mechanism for the choice of alternative cell types by homogeneous neighbouring cells. Here, we show that cells engineered with a Delta-Notch-dependent lateral inhibition circuit spontaneously bifurcate into Delta-positive and Notch-active cell populations. The synthetic lateral inhibition circuit comprises transcriptional repression of Delta and intracellular feedback of Lunatic fringe (Lfng). The Lfng-feedback subcircuit, even alone, causes the autonomous cell-type bifurcation. Furthermore, the ratio of two cell populations bifurcated by lateral inhibition is reproducible and robust against perturbation. The cell-type ratio is adjustable by the architecture of the lateral inhibition circuit as well as the degree of cell-cell attachment. Thus, the minimum lateral inhibition mechanism between adjacent cells not only serves as a binary cell-type switch of individual cells but also governs the cell-type ratio at the cell-population level.
authors: 1] RIKEN Center for Developmental Biology, Kobe 650-0047, Japan [2] Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Kyoto 606-8501, Japan [3] Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan.
authors: Mitsuhiro
authors: M
authors: Matsuda
authors: 1] RIKEN Center for Developmental Biology, Kobe 650-0047, Japan [2] Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Kyoto 606-8501, Japan [3] Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan.
authors: Makito
authors: M
authors: Koga
authors: 1] Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan [2] Hakubi Center for Advanced Research, Kyoto University, Kyoto 606-8501, Japan.
authors: Knut
authors: K
authors: Woltjen
authors: Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan.
authors: Eisuke
authors: E
authors: Nishida
authors: 1] RIKEN Center for Developmental Biology, Kobe 650-0047, Japan [2] Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Kyoto 606-8501, Japan [3] Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Saitama 332-0012, Japan.
authors: Miki
authors: M
authors: Ebisuya
mesh_terms: D000818:Animals; D016466:CHO Cells; D002450:Cell Communication / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics*; D060846:Cell Engineering; D003412:Cricetulus; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005822:Genetic Vectors; D016695:Glycosyltransferases / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D000097573:Red Fluorescent Protein
chemical_list: D016695:Glycosyltransferases; D049452:Green Fluorescent Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008156:Luciferases; D008164:Luminescent Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D000097573:Red Fluorescent Protein; C064045:delta protein; C498392:Lfng protein, mouse