Synthetic lateral inhibition governs cell-type bifurcation with robust ratios

Nat Commun. 2015 Feb 5;6:6195. doi: 10.1038/ncomms7195.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cell Communication / genetics*
  • Cell Differentiation / genetics*
  • Cell Engineering
  • Cricetulus
  • Feedback, Physiological
  • Gene Expression Regulation
  • Genes, Reporter
  • Genetic Vectors
  • Glycosyltransferases / genetics
  • Glycosyltransferases / metabolism*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lentivirus / genetics
  • Lentivirus / metabolism
  • Luciferases / genetics
  • Luciferases / metabolism
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism*
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism*
  • Signal Transduction
  • Time Factors
  • Transcription, Genetic


  • Intracellular Signaling Peptides and Proteins
  • Luminescent Proteins
  • Membrane Proteins
  • Receptors, Notch
  • delta protein
  • red fluorescent protein
  • Green Fluorescent Proteins
  • Luciferases
  • Glycosyltransferases
  • Lfng protein, mouse