Synthetic lateral inhibition governs cell-type bifurcation with robust ratios

Mitsuhiro Matsuda; Makito Koga; Knut Woltjen; Eisuke Nishida; Miki Ebisuya

doi:10.1038/ncomms7195

Synthetic lateral inhibition governs cell-type bifurcation with robust ratios

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

Authors

Mitsuhiro Matsuda¹, Makito Koga¹, Knut Woltjen², Eisuke Nishida³, Miki Ebisuya⁴

Affiliations

¹ 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.
² 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.
³ Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan.
⁴ 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.

PMID: 25652697
DOI: 10.1038/ncomms7195

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.

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*
Red Fluorescent Protein
Signal Transduction
Time Factors
Transcription, Genetic

Substances

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