VEGF signals induce trailblazer cell identity that drives neural crest migration.
Embryonic neural crest cells travel in discrete streams to precise locations throughout the head and body. We previously showed that cranial neural crest cells respond chemotactically to vascular endothelial growth factor (VEGF) and that cells within the migratory front have distinct behaviors and gene expression. We proposed a cell-induced gradient model in which lead neural crest cells read out directional information from a chemoattractant profile and instruct trailers to follow. In this study, we show that migrating chick neural crest cells do not display distinct lead and trailer gene expression profiles in culture. However, exposure to VEGF in vitro results in the upregulation of a small subset of genes associated with an in vivo lead cell signature. Timed addition and removal of VEGF in culture reveals the changes in neural crest cell gene expression are rapid. A computational model incorporating an integrate-and-switch mechanism between cellular phenotypes predicts migration efficiency is influenced by the timescale of cell behavior switching. To test the model hypothesis that neural crest cellular phenotypes respond to changes in the VEGF chemoattractant profile, we presented ectopic sources of VEGF to the trailer neural crest cell subpopulation and show diverted cell trajectories and stream alterations consistent with model predictions. Gene profiling of trailer cells that diverted and encountered VEGF revealed upregulation of a subset of 'lead' genes. Injection of neuropilin1 (Np1)-Fc into the trailer subpopulation or electroporation of VEGF morpholino to reduce VEGF signaling failed to alter trailer neural crest cell trajectories, suggesting trailers do not require VEGF to maintain coordinated migration. These results indicate that VEGF is one of the signals that establishes lead cell identity and its chemoattractant profile is critical to neural crest cell migration.
Stowers Institute for Medical Research, 1000 E. 50th St., Kansas City, MO 64110, USA.
Rebecca
R
McLennan
University of Oxford, Wolfson Centre for Mathematical Biology, Mathematical Institute, Andrew Wiles Building, Radcliffe Observatory Quarter, Woodstock Road, Oxford OX2 6GG, UK; Department of Computer Science, University of Oxford, Oxford OX1 3QD, UK.
Linus J
LJ
Schumacher
Stowers Institute for Medical Research, 1000 E. 50th St., Kansas City, MO 64110, USA.
Jason A
JA
Morrison
Stowers Institute for Medical Research, 1000 E. 50th St., Kansas City, MO 64110, USA.
Jessica M
JM
Teddy
Stowers Institute for Medical Research, 1000 E. 50th St., Kansas City, MO 64110, USA.
Dennis A
DA
Ridenour
Stowers Institute for Medical Research, 1000 E. 50th St., Kansas City, MO 64110, USA.
Andrew C
AC
Box
Stowers Institute for Medical Research, 1000 E. 50th St., Kansas City, MO 64110, USA.
Craig L
CL
Semerad
Stowers Institute for Medical Research, 1000 E. 50th St., Kansas City, MO 64110, USA.
Hua
H
Li
Stowers Institute for Medical Research, 1000 E. 50th St., Kansas City, MO 64110, USA.
William
W
McDowell
Department of Computer Science, University of Oxford, Oxford OX1 3QD, UK.
David
D
Kay
University of Oxford, Wolfson Centre for Mathematical Biology, Mathematical Institute, Andrew Wiles Building, Radcliffe Observatory Quarter, Woodstock Road, Oxford OX2 6GG, UK.
Philip K
PK
Maini
University of Oxford, Wolfson Centre for Mathematical Biology, Mathematical Institute, Andrew Wiles Building, Radcliffe Observatory Quarter, Woodstock Road, Oxford OX2 6GG, UK.
Ruth E
RE
Baker
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. Electronic address: pmk@stowers.org.
Paul M
PM
Kulesa
D000818:Animals; D002465:Cell Movement; D060833:Cellular Microenvironment; D002633:Chemotaxis; D002642:Chick Embryo; D003198:Computer Simulation; D018507:Gene Expression Regulation, Developmental; D009432:Neural Crest / Q000166:cytology*; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
D042461:Vascular Endothelial Growth Factor A
Cell migration; Chick; Computational modeling; Embryonic microenvironment; Gene expression; Molecular profile; Neural crest; Trailblazers