title: Notch1-Dll4 signalling and mechanical force regulate leader cell formation during collective cell migration.
abstract: At the onset of collective cell migration, a subset of cells within an initially homogenous population acquires a distinct 'leader' phenotype with characteristic morphology and motility. However, the factors driving the leader cell formation as well as the mechanisms regulating leader cell density during the migration process remain to be determined. Here we use single-cell gene expression analysis and computational modelling to show that the leader cell identity is dynamically regulated by Dll4 signalling through both Notch1 and cellular stress in a migrating epithelium. Time-lapse microscopy reveals that Dll4 is induced in leader cells after the creation of the cell-free region and leader cells are regulated via Notch1-Dll4 lateral inhibition. Furthermore, mechanical stress inhibits Dll4 expression and leader cell formation in the monolayer. Collectively, our findings suggest that a reduction of mechanical force near the boundary promotes Notch1-Dll4 signalling to dynamically regulate the density of leader cells during collective cell migration.
authors.affiliation: Department of Aerospace and Mechanical Engineering, The University of Arizona, Tucson, Arizona 85721-0119, USA.
authors.forename: Reza
authors.initials: R
authors.lastname: Riahi
authors.affiliation: Department of Aerospace and Mechanical Engineering, The University of Arizona, Tucson, Arizona 85721-0119, USA.
authors.forename: Jian
authors.identifier: 0000000185396590
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Aerospace and Mechanical Engineering, The University of Arizona, Tucson, Arizona 85721-0119, USA.
authors.forename: Shue
authors.initials: S
authors.lastname: Wang
authors.affiliation: 1] Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China [2] Department of Pharmacology and Toxicology, The University of Arizona, Tucson, Arizona 85724, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Long
authors.affiliation: Department of Pharmacology and Toxicology, The University of Arizona, Tucson, Arizona 85724, USA.
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
authors.affiliation: Department of Aerospace and Mechanical Engineering, The University of Arizona, Tucson, Arizona 85721-0119, USA.
authors.forename: Pak Kin
authors.initials: PK
authors.lastname: Wong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002135:Calcium-Binding Proteins; D002450:Cell Communication; D002454:Cell Differentiation; D002465:Cell Movement; D018920:Coculture Techniques; D003198:Computer Simulation; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D061986:MCF-7 Cells; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008856:Microscopy, Fluorescence; D034741:RNA, Small Interfering / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D013314:Stress, Mechanical
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; C519665:DLL4 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D034741:RNA, Small Interfering; D051881:Receptor, Notch1