Abstract
Author SummaryThe neural crest is a highly migratory population of embryonic cells, which requires Wnt signaling at several stages to promote migration and cell fate decisions. Intracellular trafficking of Wnt receptors and associated proteins can affect the timing and intensity of Wnt signaling. An obvious question is whether proton pumps and/or their partner proteins that are associated with intracellular vesicles might have a role in intracellular trafficking, Wnt signaling, and cell migration/adhesion. In this study we demonstrate such a role for Rabconnectin-3a, a protein associated with the vacuolar-ATPase (v-ATPase) proton pump complex. Loss of Rabconnectin-3a in zebrafish embryos disrupts the maturation of endocytic vesicles in neural crest cells, which has two effects: (1) decreasing Wnt signaling in these cells before migration and (2) increasing Wnt signaling after migration. Prior to migration, endosomes that fail to mature reduce Wnt signaling in neural crest cells and disrupt the localization and expression of cadherins, membrane-bound cell adhesion molecules required for these cells to initiate an epithelial-mesenchymal transition. At later stages, however, Wnt receptors accumulate at the membranes of unmigrated neural crest cells due to defective endocytosis, which correlates with high levels of Wnt signaling. Interestingly, Rabconnectin-3a-deficient neural crest cells that fail to migrate become pigment cells, presumably due to elevated Wnt signaling. Rabconnectin-3a may have a conserved role in endosomal maturation, Wnt signaling, and cell migration in many other cell populations.
Highlights
The epithelial-mesenchymal transition (EMT) is characterized by loss of epithelial cell adhesion, dynamic expression and subcellular localization of cell–cell adhesion molecules, and increased cell motility [1]
The neural crest is a highly migratory population of embryonic cells, which requires Wnt signaling at several stages to promote migration and cell fate decisions
In this study we demonstrate such a role for Rabconnectin3a, a protein associated with the vacuolar-ATPase proton pump complex
Summary
The epithelial-mesenchymal transition (EMT) is characterized by loss of epithelial cell adhesion, dynamic expression and subcellular localization of cell–cell adhesion molecules, and increased cell motility [1]. EMT is a hallmark of cancer metastasis [2] and of many cell populations during embryogenesis. NC cells initiate EMT in response to a variety of external signals, but how these are integrated spatially and temporally to give rise to different NC cell populations is poorly understood. Proper timing of signal transduction [5] and dynamic expression and subcellular localization of adhesion molecules is required for NC EMT and migration [6,7,8,9]. Secreted Wnt ligands bind to Frizzled (Fz) receptors to promote canonical Wnt signaling by stabilizing B-catenin (Bcat) in the cytosol and allowing it to translocate to the nucleus and regulate target gene expression [10]
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