miRNA Regulation of Sdf1 Chemokine Signaling Provides Genetic Robustness to Germ Cell Migration

Nat Genet. 2011 Mar;43(3):204-11. doi: 10.1038/ng.758. Epub 2011 Jan 23.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement / genetics*
  • Chemokine CXCL12 / genetics*
  • Chemokine CXCL12 / metabolism
  • Gene Expression Regulation
  • Germ Cells / physiology*
  • MicroRNAs / physiology
  • Models, Biological
  • Receptors, CXCR / genetics
  • Receptors, CXCR / metabolism
  • Signal Transduction / genetics
  • Zebrafish
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism

Substances

  • CXCR7 protein, zebrafish
  • Chemokine CXCL12
  • MicroRNAs
  • Mirn430 microRNA, zebrafish
  • Receptors, CXCR
  • Zebrafish Proteins