Rabconnectin-3a regulates vesicle endocytosis and canonical Wnt signaling in zebrafish neural crest migration

PLoS Biol. 2014 May 6;12(5):e1001852. doi: 10.1371/journal.pbio.1001852. eCollection 2014 May.


Cell migration requires dynamic regulation of cell-cell signaling and cell adhesion. Both of these processes involve endocytosis, lysosomal degradation, and recycling of ligand-receptor complexes and cell adhesion molecules from the plasma membrane. Neural crest (NC) cells in vertebrates are highly migratory cells, which undergo an epithelial-mesenchymal transition (EMT) to leave the neural epithelium and migrate throughout the body to give rise to many different derivatives. Here we show that the v-ATPase interacting protein, Rabconnectin-3a (Rbc3a), controls intracellular trafficking events and Wnt signaling during NC migration. In zebrafish embryos deficient in Rbc3a, or its associated v-ATPase subunit Atp6v0a1, many NC cells fail to migrate and misregulate expression of cadherins. Surprisingly, endosomes in Rbc3a- and Atp6v0a1-deficient NC cells remain immature but still acidify. Rbc3a loss-of-function initially downregulates several canonical Wnt targets involved in EMT, but later Frizzled-7 accumulates at NC cell membranes, and nuclear B-catenin levels increase. Presumably due to this later Wnt signaling increase, Rbc3a-deficient NC cells that fail to migrate become pigment progenitors. We propose that Rbc3a and Atp6v0a1 promote endosomal maturation to coordinate Wnt signaling and intracellular trafficking of Wnt receptors and cadherins required for NC migration and cell fate determination. Our results suggest that different v-ATPases and associated proteins may play cell-type-specific functions in intracellular trafficking in many contexts.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Adhesion
  • Cell Communication
  • Cell Differentiation
  • Cell Movement
  • Cloning, Molecular
  • Embryo, Nonmammalian
  • Endocytosis / genetics*
  • Endosomes / metabolism
  • Epithelial-Mesenchymal Transition
  • Gene Expression Regulation, Developmental*
  • Microinjections
  • Morphogenesis / genetics*
  • Morpholinos / genetics
  • Morpholinos / metabolism
  • Neural Crest / cytology
  • Neural Crest / growth & development
  • Neural Crest / metabolism*
  • Oligonucleotides, Antisense / genetics
  • Oligonucleotides, Antisense / metabolism
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Vacuolar Proton-Translocating ATPases / genetics
  • Vacuolar Proton-Translocating ATPases / metabolism
  • Wnt Signaling Pathway
  • Zebrafish / genetics*
  • Zebrafish / growth & development
  • Zebrafish / metabolism
  • Zebrafish Proteins / antagonists & inhibitors
  • Zebrafish Proteins / genetics*
  • Zebrafish Proteins / metabolism


  • Adaptor Proteins, Signal Transducing
  • Cadherins
  • Morpholinos
  • Oligonucleotides, Antisense
  • Protein Subunits
  • Recombinant Proteins
  • Zebrafish Proteins
  • rabconnectin-3a, zebrafish
  • Vacuolar Proton-Translocating ATPases