The guanine nucleotide exchange factor Net1 facilitates the specification of dorsal cell fates in zebrafish embryos by promoting maternal β-catenin activation

Cell Res. 2017 Feb;27(2):202-225. doi: 10.1038/cr.2016.141. Epub 2016 Dec 2.

Abstract

Wnt/β-catenin signaling is essential for the initiation of dorsal-ventral patterning during vertebrate embryogenesis. Maternal β-catenin accumulates in dorsal marginal nuclei during cleavage stages, but its critical target genes essential for dorsalization are silent until mid-blastula transition (MBT). Here, we find that zebrafish net1, a guanine nucleotide exchange factor, is specifically expressed in dorsal marginal blastomeres after MBT, and acts as a zygotic factor to promote the specification of dorsal cell fates. Loss- and gain-of-function experiments show that the GEF activity of Net1 is required for the activation of Wnt/β-catenin signaling in zebrafish embryos and mammalian cells. Net1 dissociates and activates PAK1 dimers, and PAK1 kinase activation causes phosphorylation of S675 of β-catenin after MBT, which ultimately leads to the transcription of downstream target genes. In summary, our results reveal that Net1-regulated β-catenin activation plays a crucial role in the dorsal axis formation during zebrafish development.

MeSH terms

  • Animals
  • Body Patterning*
  • Cell Line
  • Cell Nucleus / metabolism
  • Embryo, Nonmammalian / metabolism*
  • Female
  • GTP Phosphohydrolases / metabolism
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Phosphorylation
  • Phosphoserine / metabolism
  • Protein Multimerization
  • Wnt Signaling Pathway
  • Zebrafish / embryology*
  • Zebrafish / metabolism*
  • Zebrafish Proteins / metabolism*
  • beta Catenin / metabolism*
  • p21-Activated Kinases / metabolism

Substances

  • Guanine Nucleotide Exchange Factors
  • Net1 protein, zebrafish
  • Zebrafish Proteins
  • beta Catenin
  • Phosphoserine
  • p21-Activated Kinases
  • GTP Phosphohydrolases