Control of Chemokine-Guided Cell Migration by Ligand Sequestration

Abstract

Primordial germ cell (PGC) migration in zebrafish is directed by the chemokine SDF-1a that activates its receptor CXCR4b. Little is known about the molecular mechanisms controlling the distribution of this chemoattractant in vivo. We demonstrate that the activity of a second SDF-1/CXCL12 receptor, CXCR7, is crucial for proper migration of PGCs toward their targets. We show that CXCR7 functions primarily in the somatic environment rather than within the migrating cells. In CXCR7 knocked-down embryos, the PGCs exhibit a phenotype that signifies defects in SDF-1a gradient formation as the cells fail to polarize effectively and to migrate toward their targets. Indeed, somatic cells expressing CXCR7 show enhanced internalization of the chemokine suggesting that CXCR7 acts as a sink for SDF-1a, thus allowing the dynamic changes in the transcription of sdf-1a to be mirrored by similar dynamics at the protein level.

The Group Migration of Dictyostelium Cells Is Regulated by Extracellular Chemoattractant Degradation

“…The CXCR4 receptor on migrating cells has been shown to guide their chemotaxis; however, mutations that control receptor internalization, and thereby signaling levels, have been shown to affect the precision of chemotaxis (Minina et al, 2007). In addition, CXCR7, which also binds SDF-1, is expressed in somatic tissue and seems to influence SDF-1 gradient formation by internalizing the attractant along the migration route (Boldajipour et al, 2008). It therefore seems that regulated attractant degradation allows a variety of cells to follow precise chemotactic path in complex environments.…”

“…Many cell types use receptor-mediated degradation to maintain detectable levels of chemoattractants. In this context, cells internalize the bound receptor and as part of the receptor recycling pathway the ligand is released for degradation (Minina et al, 2007;Boldajipour et al, 2008;Borroni et al, 2008;Scola et al, 2008). Alternatively, extracellular enzymes can specifically degrade the extracellular signaling molecules, allowing the sensing machinery to go back to basal levels and retain high sensitivity (Leidal et al, 2003;Bader et al, 2007;Van Lint and Libert, 2007;Leung et al, 2008).…”

On the move: endocytic trafficking in cell migration

“…Furthermore, a gradient can be established by removing the chemoattractant in a regulated manner through receptor-mediated endocytosis. 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].…”

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

“…The phenotype of these mice is characterized by deficient hematopoiesis with defects in B-cell development and myelopoiesis, and abnormal neuronal and cardiovascular development. [9][10][11][12] More recently, CXCR7 has been described as an alternate receptor for CXCL12, which appears to function by sequestering CXCL12 13 and modifying CXCR4 signaling rather than displaying autonomous signaling in response to CXCL12. 14 Mesenchymal stromal cells (MSCs) are considered a major source for CXCL12 in the adult organism.…”