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miRNA regulation of Sdf1 chemokine signaling provides genetic robustness to germ cell migration

Abstract

microRNAs (miRNAs) function as genetic rheostats to control gene output. Based on their role as modulators, it has been postulated that miRNAs canalize development and provide genetic robustness. Here, we uncover a previously unidentified regulatory layer of chemokine signaling by miRNAs that confers genetic robustness on primordial germ cell (PGC) migration. In zebrafish, PGCs are guided to the gonad by the ligand Sdf1a, which is regulated by the sequestration receptor Cxcr7b. We find that miR-430 regulates sdf1a and cxcr7 mRNAs. Using target protectors, we demonstrate that miR-430–mediated regulation of endogenous sdf1a (also known as cxcl12a) and cxcr7b (i) facilitates dynamic expression of sdf1a by clearing its mRNA from previous expression domains, (ii) modulates the levels of the decoy receptor Cxcr7b to avoid excessive depletion of Sdf1a and (iii) buffers against variation in gene dosage of chemokine signaling components to ensure accurate PGC migration. Our results indicate that losing miRNA-mediated regulation can expose otherwise buffered genetic lesions leading to developmental defects.

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Figure 1: miR-430 target validation of chemokine signaling genes.
Figure 2: Target protectors prevent miRNA-mediated repression of target GFP reporters.
Figure 3: Blocking miR-430–mediated repression of sdf1a and cxcr7b causes PGC mislocalization and expanded sdf1a expression.
Figure 4: miR-430 and Cxcr7b act in a functionally redundant manner to refine Sdf1a expression.
Figure 5: miR-430 buffers against overexpression of the chemokine signaling components.
Figure 6: Regulation by miR-430 guards against variation in gene dosage.
Figure 7: Model of miR-430–mediated repression of chemokine signaling.

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Acknowledgements

We thank H. Patnode for fish husbandry, C. Takacs and C. Stahlhut for discussion and critical reading of the manuscript, H. Xue for analysis of the Sdf1a 3′ UTR and D. Stemple for cxcr7b mutant zebrafish. This work was supported by the National Research Service Award US National Institutes of Health (NIH)/National Institute of General Medicine Sciences T32 GM007223 Training Grant (A.A.S.), NIH grants R01GM081602-03/03S1, the Yale Scholar program, the Pew Scholars Program in Biomedical Sciences (A.J.G.) and a Whitehead Fellowship Award (H.K.).

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A.A.S. and A.J.G. designed the experiments and interpreted the results. A.A.S. performed all experiments except the genetic interactions in the cxcr7b and cxcr4b mutant backgrounds, which were performed by H.K. A.A.S. wrote the manuscript with input from H.K. and A.J.G.

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Correspondence to Antonio J Giraldez.

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Staton, A., Knaut, H. & Giraldez, A. miRNA regulation of Sdf1 chemokine signaling provides genetic robustness to germ cell migration. Nat Genet 43, 204–211 (2011). https://doi.org/10.1038/ng.758

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