Directional tissue migration through a self-generated chemokine gradient.
The directed migration of cell collectives is a driving force of embryogenesis. The predominant view in the field is that cells in embryos navigate along pre-patterned chemoattractant gradients. One hypothetical way to free migrating collectives from the requirement of long-range gradients would be through the self-generation of local gradients that travel with them, a strategy that potentially allows self-determined directionality. However, a lack of tools for the visualization of endogenous guidance cues has prevented the demonstration of such self-generated gradients in vivo. Here we define the in vivo dynamics of one key guidance molecule, the chemokine Cxcl12a, by applying a fluorescent timer approach to measure ligand-triggered receptor turnover in living animals. Using the zebrafish lateral line primordium as a model, we show that migrating cell collectives can self-generate gradients of chemokine activity across their length via polarized receptor-mediated internalization. Finally, by engineering an external source of the atypical receptor Cxcr7 that moves with the primordium, we show that a self-generated gradient mechanism is sufficient to direct robust collective migration. This study thus provides, to our knowledge, the first in vivo proof for self-directed tissue migration through local shaping of an extracellular cue and provides a framework for investigating self-directed migration in many other contexts including cancer invasion.
EMBL Heidelberg, Meyerhofstraße 1, 69117 Heidelberg, Germany.
Erika
E
Donà
Joseph D
JD
Barry
Guillaume
G
Valentin
Charlotte
C
Quirin
Anton
A
Khmelinskii
Andreas
A
Kunze
Sevi
S
Durdu
Lionel R
LR
Newton
Ana
A
Fernandez-Minan
Wolfgang
W
Huber
Michael
M
Knop
Darren
D
Gilmour
D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D002630:Chemotactic Factors / Q000235:genetics / Q000378:metabolism*; D004625:Embryo, Nonmammalian; D018507:Gene Expression Regulation, Developmental; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000502:physiology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
C519524:CXCR7 protein, zebrafish; D054377:Chemokine CXCL12; D002630:Chemotactic Factors; D054387:Receptors, CXCR; D029961:Zebrafish Proteins; C579453:cxcl12a protein, zebrafish