title: Coordinated control of Notch/Delta signalling and cell cycle progression drives lateral inhibition-mediated tissue patterning.
abstract: Coordinating cell differentiation with cell growth and division is crucial for the successful development, homeostasis and regeneration of multicellular tissues. Here, we use bristle patterning in the fly notum as a model system to explore the regulatory and functional coupling of cell cycle progression and cell fate decision-making. The pattern of bristles and intervening epithelial cells (ECs) becomes established through Notch-mediated lateral inhibition during G2 phase of the cell cycle, as neighbouring cells physically interact with each other via lateral contacts and/or basal protrusions. Since Notch signalling controls cell division timing downstream of Cdc25, ECs in lateral contact with a Delta-expressing cell experience higher levels of Notch signalling and divide first, followed by more distant neighbours, and lastly Delta-expressing cells. Conversely, mitotic entry and cell division makes ECs refractory to lateral inhibition signalling, fixing their fate. Using a combination of experiments and computational modelling, we show that this reciprocal relationship between Notch signalling and cell cycle progression acts like a developmental clock, providing a delimited window of time during which cells decide their fate, ensuring efficient and orderly bristle patterning.
authors.affiliation: MRC-Laboratory for Molecular and Cell Biology, University College London, London WC1E 6BT, UK Institute of Physics of Living Systems, University College London, London WC1E 6BT, UK g.hunter@ucl.ac.uk b.baum@ucl.ac.uk.
authors.forename: Ginger L
authors.identifier: 0000-0001-7022-9482
authors.initials: GL
authors.lastname: Hunter
authors.affiliation: Centre for Mathematics, Physics, and Engineering in the Life Sciences and Experimental Biology, University College London, London WC1E 6BT, UK Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK.
authors.forename: Zena
authors.initials: Z
authors.lastname: Hadjivasiliou
authors.affiliation: MRC-Laboratory for Molecular and Cell Biology, University College London, London WC1E 6BT, UK.
authors.forename: Hope
authors.initials: H
authors.lastname: Bonin
authors.affiliation: Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Li
authors.initials: L
authors.lastname: He
authors.affiliation: Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Norbert
authors.initials: N
authors.lastname: Perrimon
authors.affiliation: Institute of Physics of Living Systems, University College London, London WC1E 6BT, UK London Centre for Nanotechnology, University College London, London WC1E 6BT, UK Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Charras
authors.affiliation: MRC-Laboratory for Molecular and Cell Biology, University College London, London WC1E 6BT, UK Institute of Physics of Living Systems, University College London, London WC1E 6BT, UK g.hunter@ucl.ac.uk b.baum@ucl.ac.uk.
authors.forename: Buzz
authors.initials: B
authors.lastname: Baum
mesh_terms: D000818:Animals; D019521:Body Patterning; D002453:Cell Cycle; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D012679:Sense Organs / Q000166:cytology; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D014738:Vibrissae / Q000166:cytology / Q000196:embryology
chemical_list: D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497759:N protein, Drosophila; D051880:Receptors, Notch; C064045:delta protein
keywords: Cell cycle; G2 phase; Lateral inhibition; Notch signalling; Patterning