Editors' ChoiceDevelopment

No Migration Without Sequestration

Science Signaling  05 Nov 2013:
Vol. 6, Issue 300, pp. ec268
DOI: 10.1126/scisignal.2004878

Migrating cells sense patterns in the concentration of signaling molecules as a means of navigating complex environments. In some tissues, gradients of signaling molecules are established by secretion from a point source, elimination by a local sink, or a combination of the two. In contrast, in zebrafish embryos, a mass of migrating cells known as the posterior lateral line (PLL) primordium, which ultimately form sensory organs, traverse from anterior to posterior along a uniform stripe of the chemoattractant Sdf1a. The cells of the PLL have two classes of Sdf1 receptors, with the signaling-competent Cxcr4b present throughout the mass of cells and Cxcr7, which does not stimulate intracellular signaling, in the trailing cells. Venkiteswaran et al. used quantitative imaging of transgenic zebrafish to show that Sdf1a fused to green fluorescent protein (GFP), under the control of endogenous Sdf1a regulatory elements, formed discrete punctae in the rear of the PLL, suggesting that these cells may locally modify the available concentration of Sdf1a. When bound to Sdf1a, Cxcr4b is internalized, which is required for signal transduction. Ratiometric imaging Cxcr4b fused to the fluorescent protein Kate2 (Cxcr4b-Kate2) and membrane-localized GFP showed that Cxcr4b internalization and thus Sdf1a signaling was greatest at the front of the PLL. The mRNAs encoding Cxcr7a and 7b were expressed in the rear of the PLL, and simultaneous inhibition of both genes by morpholino-mediated antisense disrupted PLL migration, the formation of Sdf1a-GFP punctae in the trailing cells, and the gradient of Cxcr4b-Kate2 to membrane-GFP ratiometric abundance, supporting the idea that Cxcr7a and 7b function to clear Sdf1 from the rear of the migrating PLL and thereby create a local Sdf1 gradient. Brief heat shock induced overexpression of Sdf1a, which inhibits PLL migration, and abrogated the gradient of Sdf1 signaling, and the reestablishment of the Sdf1 gradient, which coincided with the resumption of PLL migration, depended on Cxcr7a and 7b. Mathematical modeling of a uniform source of freely diffusing Sdf1 and localized binding by Cxcr7 confirmed that PLL cells could establish a stable, linear gradient within a time frame that would be minimally affected by PLL migration. Thus, these results show that migratory cells can use selective sequestration to establish directional guidance cues from an otherwise distributed source of chemoattractant molecules.

G. Venkiteswaran, S. W. Lewellis, J. Wang, E. Reynolds, C. Nicholson, H. Knaut, Generation and dynamics of an endogenous, self-generated signaling gradient across a migrating tissue. Cell 155, 674–687 (2013). [PubMed]