Dkk2 promotes neural crest specification by activating Wnt/β-catenin signaling in a GSK3β independent manner

Elife. 2018 Jul 23:7:e34404. doi: 10.7554/eLife.34404.

Abstract

Neural crest progenitors are specified through the modulation of several signaling pathways, among which the activation of Wnt/β-catenin signaling by Wnt8 is especially critical. Glycoproteins of the Dickkopf (Dkk) family are important modulators of Wnt signaling acting primarily as Wnt antagonists. Here we report that Dkk2 is required for neural crest specification functioning as a positive regulator of Wnt/β-catenin signaling. Dkk2 depletion in Xenopus embryos causes a loss of neural crest progenitors, a phenotype that is rescued by expression of Lrp6 or β-catenin. Dkk2 overexpression expands the neural crest territory in a pattern reminiscent of Wnt8, Lrp6 and β-catenin gain-of-function phenotypes. Mechanistically, we show that Dkk2 mediates its neural crest-inducing activity through Lrp6 and β-catenin, however unlike Wnt8, in a GSK3β independent manner. These findings suggest that Wnt8 and Dkk2 converge on β-catenin using distinct transduction pathways both independently required to activate Wnt/β-catenin signaling and induce neural crest cells.

Keywords: Dkk; Wnt; Xenopus; developmental biology; neural crest; xenopus.

Publication types

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

MeSH terms

  • Animals
  • Cell Lineage
  • Cells, Cultured
  • Embryo, Nonmammalian / cytology
  • Embryo, Nonmammalian / physiology
  • Gene Expression Regulation, Developmental*
  • Glycogen Synthase Kinase 3 beta / genetics
  • Glycogen Synthase Kinase 3 beta / metabolism*
  • Low Density Lipoprotein Receptor-Related Protein-6 / genetics
  • Low Density Lipoprotein Receptor-Related Protein-6 / metabolism
  • Neural Crest / cytology
  • Neural Crest / physiology*
  • Wnt Signaling Pathway
  • Xenopus Proteins / genetics
  • Xenopus Proteins / metabolism*
  • Xenopus laevis
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • Dkk2 protein, Xenopus
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Xenopus Proteins
  • beta Catenin
  • Glycogen Synthase Kinase 3 beta