title: Neural crest migration is driven by a few trailblazer cells with a unique molecular signature narrowly confined to the invasive front.
abstract: Neural crest (NC) cell migration is crucial to the formation of peripheral tissues during vertebrate development. However, how NC cells respond to different microenvironments to maintain persistence of direction and cohesion in multicellular streams remains unclear. To address this, we profiled eight subregions of a typical cranial NC cell migratory stream. Hierarchical clustering showed significant differences in the expression profiles of the lead three subregions compared with newly emerged cells. Multiplexed imaging of mRNA expression using fluorescent hybridization chain reaction (HCR) quantitatively confirmed the expression profiles of lead cells. Computational modeling predicted that a small fraction of lead cells that detect directional information is optimal for successful stream migration. Single-cell profiling then revealed a unique molecular signature that is consistent and stable over time in a subset of lead cells within the most advanced portion of the migratory front, which we term trailblazers. Model simulations that forced a lead cell behavior in the trailing subpopulation predicted cell bunching near the migratory domain entrance. Misexpression of the trailblazer molecular signature by perturbation of two upstream transcription factors agreed with the in silico prediction and showed alterations to NC cell migration distance and stream shape. These data are the first to characterize the molecular diversity within an NC cell migratory stream and offer insights into how molecular patterns are transduced into cell behaviors.
authors.affiliation: Stowers Institute for Medical Research, 1000 E. 50th St, Kansas City, MO 64110, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: McLennan
authors.affiliation: Oxford University, Wolfson Centre for Mathematical Biology, Mathematical Institute, Woodstock Road, Oxford OX2 6GG, UK Computer Science, Oxford University, Wolfson Building, Parks Road, Oxford OX1 3QD, UK.
authors.forename: Linus J
authors.initials: LJ
authors.lastname: Schumacher
authors.affiliation: Stowers Institute for Medical Research, 1000 E. 50th St, Kansas City, MO 64110, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Morrison
authors.affiliation: Stowers Institute for Medical Research, 1000 E. 50th St, Kansas City, MO 64110, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Teddy
authors.affiliation: Stowers Institute for Medical Research, 1000 E. 50th St, Kansas City, MO 64110, USA.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Ridenour
authors.affiliation: Stowers Institute for Medical Research, 1000 E. 50th St, Kansas City, MO 64110, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Box
authors.affiliation: Stowers Institute for Medical Research, 1000 E. 50th St, Kansas City, MO 64110, USA.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Semerad
authors.affiliation: Stowers Institute for Medical Research, 1000 E. 50th St, Kansas City, MO 64110, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Stowers Institute for Medical Research, 1000 E. 50th St, Kansas City, MO 64110, USA.
authors.forename: William
authors.initials: W
authors.lastname: McDowell
authors.affiliation: Oxford University, Wolfson Centre for Mathematical Biology, Mathematical Institute, Woodstock Road, Oxford OX2 6GG, UK Computer Science, Oxford University, Wolfson Building, Parks Road, Oxford OX1 3QD, UK.
authors.forename: David
authors.initials: D
authors.lastname: Kay
authors.affiliation: Oxford University, Wolfson Centre for Mathematical Biology, Mathematical Institute, Woodstock Road, Oxford OX2 6GG, UK.
authors.forename: Philip K
authors.initials: PK
authors.lastname: Maini
authors.affiliation: Oxford University, Wolfson Centre for Mathematical Biology, Mathematical Institute, Woodstock Road, Oxford OX2 6GG, UK.
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Baker
authors.affiliation: Stowers Institute for Medical Research, 1000 E. 50th St, Kansas City, MO 64110, USA Department of Anatomy and Cell Biology, University of Kansas School of Medicine, Kansas City, KS 66160, USA pmk@stowers.org.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Kulesa
mesh_terms: D000818:Animals; D030161:Avian Proteins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D002642:Chick Embryo; D003198:Computer Simulation; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D009432:Neural Crest / Q000166:cytology* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D059010:Single-Cell Analysis
chemical_list: D030161:Avian Proteins; D012333:RNA, Messenger
keywords: Cell migration; Chicken; Mathematical modeling; Molecular profiling; Neural crest; Numerical simulation; Single cell