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Inhibiting the translation of cxcr4a along with cxcl12b RNAs using antisense morpholino oligonucleotides elicited the previously described abnormal displacement of endoderm from the dorsal forerunner cells, as seen in Figure 1B Nair and Schilling, Unlike the case of chemokine-guided migration, in the context of controlling the interaction of the endoderm with the mesoderm, the distribution of the ligand is not critical.

Accordingly, global expression of the chemokine acting in a paracrine or autocrine manner is expected to effectively control the process. Interestingly, consistent with the idea that the intracellular signals generated by the two receptors are equivalent, the expression of cxcr4b and c xcl12a RNAs in embryos knocked down for cxcr4a and cxcl12b reversed the phenotype as well. Thus, Cxcr4b signaling in endodermal cells could effectively replace that of Cxcr4a as determined by the reduction in the displacement between endodermal cells and forerunner cells.

The results presented above show that distinct CXC receptors can control processes they are not normally involved in. Nevertheless, Cxcr4a and Cxcr4b show relatively high similarity in their protein sequence Figure 2—figure supplement 1. Therefore, to examine the equivalence of chemokine receptor signaling more rigorously, we performed analogous experiments where we exchanged CC and CXC receptors in different processes. Here, Ccr9 and Ccr7 and their ligands Ccl25 and Ccl19, respectively , which do not share high-sequence similarity with Cxcr4a, Cxcr4b Figure 2—figure supplement 2 were tested in the context of Cxcr4-controlled PGC directional migration and endoderm cell adhesion.

To examine the general nature of chemokine receptor signals, we tested the potency of Ccr7 and Ccr9 in regulating endodermal cell movement. We expressed these receptors with their cognate ligands in early embryos and observed their effects on endodermal cell positioning in the embryos knocked down for Cxcr4a, the receptor that normally regulates this process.

The ubiquitous expression of chemokine receptors and their ligand in the early embryos by way of injecting the RNA results in a uniform expression pattern, which in the context of this process is similar to that of the endogenous receptor-ligand pair Cxcr4a and Cxcl12b.


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Remarkably, both Ccr9 and Ccr7 reversed the Cxcr4a phenotype concerning the displacement between endoderm cells and dorsal forerunner cells, effectively controlling endodermal cell positioning Figure 2A,B. To further test the capability of receptors to direct cell migration, we expressed receptors in PGCs and their cognate ligands in one half of the embryo in the absence of the regular endogenous signals guiding the cells i. In this experimental setup, we thus generated spatially restricted source of chemokine, simulating the uneven distribution of the endogenous guidance cue within the embryo see Figure 3 for a schematic representation of the experimental setup.

If the receptor can direct cell migration, it would lead to PGC accumulation within the part of the embryo expressing the ligand, as compared with a random distribution in control Doitsidou et al. Interestingly, in contrast with PGCs expressing control RNA that were randomly distributed throughout the embryo, under conditions where the endogenous Cxcl12a signals were knocked down, PGCs expressing Ccr9 were preferentially present on the part of the embryo engineered to express Ccl25 Figure 3A,C. Similar results were observed when testing the activity of Ccr7 and its ligand Ccl19 Figure 3A,D and Cxcr4a and its ligand Cxcl12b Figure 3A,B , demonstrating that receptors from the same and from different families can control directional PGC migration.

The experimental scheme is provided at the top. Merged images show the position of PGCs with respect to control or ligand-expressing domains red. B—D Graphs show the quantitation of the migration of PGCs as the percentage of GFP-labeled cells located within the ligand-expressing part of the embryos. Equimolar amounts of control RNA were used.

Since the biological contexts studied above are based on cell migration, we further tested the equivalency of chemokine receptor signals in the context of dorsoventral fate specification in the early zebrafish embryo. Ccr7 was previously shown to be important for dorsoventral axis specification in early zebrafish embryos Wu et al. We counted the number of pixels showing GFP expression above the auto threshold in those embryos following different experimental manipulations.

B—D Graphs showing the area of the goosecoid expression domain determined by quantifying the number of pixels with GFP signal above the auto threshold in the different treatments. For raw data see Figure 4—source data 1. In contrast to the notion that different receptors initiate different signaling cascades to mediate various biological processes, our results suggest that different chemokine receptors initiate similar signaling.

Animation explain how Chemokines work

Accordingly, the specific response to receptor signaling might depend on its interpretation by the cell type within which the receptor was activated. To test this idea, we examined the signaling downstream of chemokine receptors in the context of directional cell migration. Merged images show the position of PGCs with respect to control cntl , or ligand-expressing cells. B—E Graphs showing the quantitation of directed cell migration, by presenting the percentage of PGCs located within the ligand-expressing domains. Equimolar amounts of cntl RNA were used.

The finding that different types of chemokine receptors depend on the same signaling cascade to control the same process highlights the importance of tight regulation over their expression. This would ensure that distinct processes are regulated by the specific ligands that are expressed at the correct time and location. To demonstrate this point, we ectopically expressed the Cxcr4a receptor in the PGCs rendering them responsive to its cognate ligand Cxcl12b in addition to the endogenous Cxcr4b ligand Cxcl12a.

Interestingly, despite the expression of Cxcl12a within regions toward which the PGCs migrate, making the cells responsive to Cxcl12b affected their migration. Specifically, we found that PGCs co-expressing the two chemokine receptors were more dispersed within the embryo, consistent with the idea that they responded to spatially distinct conflicting signals encoded by the two different ligands.

Indeed, PGCs could be found in locations e. The results provided above support the notion that chemokine receptors from different groups can initiate the same signaling pathways. These findings raise the possibility that chemokine receptors in a particular cell type may act redundantly among themselves or with receptors belonging to other GPCRs classes to control specific processes, thereby conferring genetic robustness Krakauer and Plotkin, According to this proposition, receptors that are not considered to play a role in certain processes since their function appears dispensable for them, are actually important for those events, but are redundant.

To examine this proposition, we studied the role of two classes of GPCRs expressed during early stages of embryogenesis in a process where they were not known to function before. We analyzed the involvement of the chemokine receptor Cxcr4b and phospholipid receptors S1p and LPA receptors in the process of gastrulation.

To this end, we overexpressed LPPs lipid phosphate phosphatases , which dephosphorylate active lipids such as S1p and LPA, a treatment that should reduce signaling by lipid receptors Lpar and S1pr Brindley and Pilquil, Conducting this treatment in embryos lacking Cxcr4 function allows for studying the effect of simultaneous inhibition of two seemingly unrelated receptors. Interestingly, however, overexpression of LPPs in cxcr4b mutant embryos led to a strong delay in epiboly movements Figure 6A and B and somitogenesis as compared with a similar manipulation in wild-type embryos Figure 6C and D.

These results are consistent with the idea that the two unrelated receptors, despite belonging to different groups of GPCRs, cooperate in ensuring proper progression of early processes in early embryonic development. Cxcr4b-deficient embryos overexpressing Lpps exhibited a delay in gastrulation and failed to close the yolk plug. B Graph showing the percentage of embryos with closed yolk plug between 9. C Brightfield images of embryos at 12 hpf.

For raw data see Figure 6—source data 1. According to our findings, chemokine-induced signaling elicits a qualitatively similar cascade that is interpreted differently by different types of cells. At the same time, a specific cell type can interpret chemokine signals in a distinct way that is dictated by the specific chemokine receptor signal interpretation module CRIM. For example, if a chemokine receptor-induced signaling cascade leads to directional migration toward a ligand, the same signaling cannot induce migration away from the source of ligand in the same cell type Poznansky et al.

However, our model appears to be incompatible with cell behavior during fugetaxis cell movement away from the chemoattractant [ Vianello et al. Relevant for the guided migration of PGCs, T-cells were shown to actively migrate away from high concentrations of Cxcl12 Poznansky et al. To examine the behavior of PGCs upon exposure to a high concentration of a ligand, simulating the conditions the cells would experience upon arrival at their target, we expressed the ligand in the forming endoderm of the embryo.

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In this experiment, we expressed low 25 pg and high pg amounts of cxcl12a in endoderm and observed the behavior of Cxcr4-expressing PGCs in a 10 hpf embryo. As expected, the PGCs were found to be located on the Cxcl12a-expressing area when the level of the ligand was low Figure 7A , Figure 7—Video 1 , they continued to migrate within this region and only very rarely would leave the Cxcl12a-expressing domain Figure 7B and C.


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Surprisingly, unlike the behavior PGCs exhibited with respect to low-Cxcl12a-expressing domains, when high levels of the ligand pg were expressed, the PGCs were not localized within the area where the ligand was expressed Figure 7A. Instead, the cells initially actively migrated toward ligand-expressing area, but often turned away from the region where the ligand was expressed, a behavior resembling reverse migration, as observed, for example, for neutrophils at a resolution phase of inflammation de Oliveira et al.

A Tracks of PGCs with respect to domains in the embryo expressing low or high levels of Cxcl12a, in embryos lacking the endogenous ligand. PGCs migrated into domains expressing low levels of the attractant and remained within them, while the cells turned away when the domains expressed high levels of Cxcl12a.

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B Graph showing percentage of cells that moved away from the Cxcl12a expressing domains 2. C Graph showing the percentage of cells that remained for 90 minutes or more within the Cxcl12a expressing area The cells interacted with low and high Cxcl12a expressing domains as in A. E Graph showing the level of Cxcr4b on the PGC membrane as a ratio between the EGFP signal and that of the farnesylated mCherry in cells exposed to low and high concentrations of the ligand.

For raw data see Figure 7—source data 1. Since PGCs performed reverse migration only when exposed to a high concentration of the ligand, we reasoned that rapid receptor internalization due to exposure to high levels of the ligand could lead to this behavior. According to this model, when cells reach the location of high ligand concentration, they can move away as they lost the ability to respond to the chemokine signal and migrate randomly.

To examine this possibility, we compared the effect of ligand concentration on the levels of the Cxcr4b receptor on the membrane of PGCs. The ratio between the mCherry and the EGFP signals reported the relative amount of functional receptor present on the membrane of the cell. Indeed, PGCs exposed to a high concentration of the ligand retained significantly fewer receptors on their membranes as compared with PGCs exposed to a low concentration of the ligand Figure 7D and E.

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Thus, the level of receptor internalization could be correlated with reverse migration and could constitute the basis for this behavior. In this work, we show that the same chemokine receptor can direct distinct responses in different cell types, while different receptors elicit the same biological response in a specific type of cells. These findings are consistent with the idea, that the biological consequences of chemokine receptor signaling depend on the cell type rather than on qualitative differences in the signal produced by specific receptors.

We demonstrate that the identity of the activated receptor is immaterial for the actual interpretation of the signal that results in distinct biological responses in different cells. Our findings suggest that based upon their specific differentiation state, different cell types contain specific chemokine receptor signal interpretation modules CRIM that interpret the generic signals produced by chemokine receptors.

The suggestion that the same receptor can elicit different cellular responses is presented graphically in Figure 8A. While it is possible that different receptors induce the response more efficiently or less, the qualitative features of the signaling, at least for the receptors and processes we examined, appear to be generic. Consistently, the cell-specific biological response to the signal appears to be robust as it can be observed when different levels of the receptor were expressed in the cells Figure 3—figure supplement 1.

This situation is analogous to heterozygosity for mutated chemokine and chemokine receptor alleles that has no phenotypic consequences Knaut et al. A Graphical summary of results. B Schematic representation of concurrent trafficking of different cell types possessing identical CRIM and expressing different chemokine receptors.