Directional tissue migration through a self-generated chemokine gradient

Abstract

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.

On the move: endocytic trafficking in cell migration

“…The first demonstration of such a chemokine sequestering mechanism was identified in zebrafish, where the somatically expressed scavenger receptor CXCR7/ACKR3 sequesters CXCL12 by internalization from the tissue, permitting germ cell migration away from the chemokine sink [8]. Subsequently, the zebrafish primordium was shown to generate a chemokine gradient across itself by sequestering CXCL12 locally in its rear via CXCR7/ ACKR3 while CXCL12-producing cells at the stripe underneath the primordium provide the guidance cue to the migrating primordium [9,10]. An analogous mechanism has been recently identified for CCR7-driven dendritic cell and lymphocyte migration in mammalian lymphoid organs [11].…”

Limits to the precision of gradient sensing with spatial communication and temporal integration

“…Cells are even more sensitive when they are in a group: Cultures of many neurons respond to chemical gradients equivalent to a difference of only one molecule across an individual neuron's axonal growth cone (2), clusters of malignant lymphocytes have a wider chemotactic sensitivity than single cells (3), and groups of communicating epithelial cells detect gradients that are too weak for a single cell to detect (4). More generally, collective chemosensing properties are often very distinct from those in individual cells (3,(5)(6)(7). These observations have generated a renewed interest in the question of what sets the fundamental limit to the precision of gradient sensing in large, spatially extended, often collective sensory systems.…”

A hybrid model of cell migration in zebrafish embryogenesis

“…Moreover, our model could reproduce the mechanism of self-generation of chemical gradient by the tip cells of the primordium: the total cell migration can be ensured even with an initial constant chemokine distribution along the longitudinal axis. This effect, hypothesized for the cell migration in embryos, has been recently proved in vivo on the zebrafish by [8].…”