Dullard/Ctdnep1 Modulates WNT Signalling Activity for the Formation of Primordial Germ Cells in the Mouse Embryo

PLoS One. 2013;8(3):e57428. doi: 10.1371/journal.pone.0057428. Epub 2013 Mar 4.

Abstract

Dullard/Ctdnep1 is a member of the serine/threonine phosphatase family of the C-terminal domain of eukaryotic RNA polymerase II. Embryos lacking Dullard activity fail to form primordial germ cells (PGCs). In the mouse, the formation of PGCs is influenced by BMP4 and WNT3 activity. Although Dullard is reputed to negatively regulate BMP receptor function, in this study we found mutations in Dullard had no detectable effect on BMP4 and p-Smad activity. Furthermore Dullard mutations did not influence the dosage-dependent inductive effect of Bmp4 in PGC formation. However, Dullard may function as a positive regulator of WNT signalling. Combined loss of one copy each of Dullard and Wnt3 had a synergistic effect on the reduction of PGC numbers in the compound heterozygous embryo. In addition, loss of Dullard function was accompanied by down-regulation of WNT/β-catenin signalling activity and a reduction in the level of Dishevelled 2 (Dvl2). Therefore, Dullard may play a role in the fine-tuning of WNT signalling activity by modulating the expression of ligands/antagonists and the availability of Dvl2 protein during specification of the germ cell lineage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Bone Morphogenetic Protein 4 / genetics
  • Bone Morphogenetic Protein 4 / metabolism
  • Cell Lineage / genetics
  • Dishevelled Proteins
  • Embryo, Mammalian
  • Gene Expression Regulation, Developmental*
  • Germ Cells / cytology
  • Germ Cells / metabolism*
  • Heterozygote
  • Homozygote
  • Mice
  • Morphogenesis / genetics
  • Mutation
  • Phosphoprotein Phosphatases / deficiency
  • Phosphoprotein Phosphatases / genetics*
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Signal Transduction / genetics*
  • Smad Proteins / genetics
  • Smad Proteins / metabolism
  • Wnt3 Protein / genetics*
  • Wnt3 Protein / metabolism
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Bmp4 protein, mouse
  • Bone Morphogenetic Protein 4
  • Dishevelled Proteins
  • Dvl2 protein, mouse
  • Phosphoproteins
  • Smad Proteins
  • Wnt3 Protein
  • Wnt3 protein, mouse
  • beta Catenin
  • Dullard protein, mouse
  • Phosphoprotein Phosphatases

Grant support

This work was supported by Grants-in-Aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (#23013018 to SST), the Japan Society for Promotion of Science (23570258 to SST), and Mr. James Fairfax (to Children’s Medical Research Institute). PPLT is a Senior Principal Research Fellow of the National Health and Medical Research Council of Australia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.