The Chemokine SDF1a Coordinates Tissue Migration through the Spatially Restricted Activation of Cxcr7 and Cxcr4b

Abstract

Tissue migration is a collective behavior that plays a key role in the formation of many organ systems. Although tissue movements are guided by extrinsic cues, in many contexts, their receptors need to be active only at the leading edge to ensure morphogenesis. This has led to the prevalent view that extrinsic signals exert their influence by controlling a small number of leader cells. The zebrafish lateral-line primordium is a cohesive cohort of over 100 cells that is guided through CXCR4-SDF1 signaling. Recent work has shown that Cxcr4b activity is only required in cells at the very tip, raising the question of what controls cell behavior within trailing regions. Here, we present the first mutant in zebrafish SDF1a/CXCL12a and show, surprisingly, that the resultant phenotype is stronger than a null mutation in its cognate receptor, Cxcr4b, indicating the involvement of other SDF1a receptors. A candidate approach identified Cxcr7/RDC1, whose expression is restricted to cells behind the leading edge. Morpholino knockdown of Cxcr7 leads to a novel phenotype in which the migration of trailing cells is specifically affected, causing tissue stretching, a defect rescued by the reintroduction of wild-type cells specifically at the back of the primordium. Finally, we present evidence that Cxcr4b and Cxcr7 act independently to regulate group migration. We provide the first example where a single extrinsic guidance cue, SDF1a, directly controls the migration of both leading and trailing edges of a tissue through the activation of two independent receptors, CXCR4b and CXCR7.

CXCR4 signaling in the regulation of stem cell migration and development

“…The full extent of the importance of CXCR7 signaling in development and adult function remains to be determined. (Miao et al, 2007;Sierro et al, 2007;Valentin et al, 2007).…”

Molecular cloning and embryonic expression of zebrafish PCSK5 co‐orthologues: Functional assessment during lateral line development

“…However, disruption of the lateral line formation resulting from PC5.1 knockdown suggests that processing of a substrate for this convertase has a critical function in this regard. Knockdown of expression of the key factors that control the cell movements underlying the formation of the lateral line primordium, namely SDF-1 and its receptors CXCR4 and CXCR7, has been found to disrupt the laying down of neuromasts (Valentin et al, 2007). However, neither SDF-1 nor its receptors require convertase activation and cannot be directly biochemically linked to the actions of PC5.1.…”

lef1 controls patterning and proliferation in the posterior lateral line system of zebrafish

“…In zebrafish, primordium migration depends on SDF1 signaling by cells along the path of migration (David et al, 2002;Li et al, 2004;Haas and Gilmour, 2006; reviewed in Ghysen and Dambly-Chaudière, 2007). The direction of migration depends on the anisotropic distribution of two SDF1 receptors, CXCR4 which is present in the leading two-thirds of the primordium, and CXCR7 which is present in the trailing third Valentin et al, 2007).…”

“…Alternatively or additionally, CXCR7 may contribute to migration independently of CXCR4 (Valentin et al, 2007). It has been proposed that SDF1/CXCR4 signaling prevents cxcr7 expression in the leading cells of the primordium, thereby maintaining nearly complementary expressions of cxcr4b and cxcr7b in the leading and trailing regions of the primordium, respectively .…”

“…The repression of cxcr7b by SDF1/ CXCR4 signaling has been questioned (Valentin et al, 2007), but was recently confirmed in conditions of ESR1 loss of function (Gamba et al, 2010). In the absence of ESR1, cxcr4b is ubiquitously expressed in the primordium, and cxcr7b expression in the trailing region is abolished.…”