Dopamine D2 receptor modulates Wnt expression and control of cell proliferation

Sci Rep. 2019 Nov 14;9(1):16861. doi: 10.1038/s41598-019-52528-4.

Abstract

The Wnt/β-catenin pathway is one of the most conserved signaling pathways across species with essential roles in development, cell proliferation, and disease. Wnt signaling occurs at the protein level and via β-catenin-mediated transcription of target genes. However, little is known about the underlying mechanisms regulating the expression of the key Wnt ligand Wnt3a or the modulation of its activity. Here, we provide evidence that there is significant cross-talk between the dopamine D2 receptor (D2R) and Wnt/β-catenin signaling pathways. Our data suggest that D2R-dependent cross-talk modulates Wnt3a expression via an evolutionarily-conserved TCF/LEF site within the WNT3A promoter. Moreover, D2R signaling also modulates cell proliferation and modifies the pathology in a renal ischemia/reperfusion-injury disease model, via its effects on Wnt/β-catenin signaling. Together, our results suggest that D2R is a transcriptional modulator of Wnt/β-catenin signal transduction with broad implications for health and development of new therapeutics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Proliferation
  • Dependovirus / genetics
  • Dependovirus / metabolism
  • Disease Models, Animal
  • Embryo, Mammalian
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Genetic Vectors / chemistry
  • Genetic Vectors / metabolism
  • Humans
  • Kidney Tubules, Proximal / metabolism*
  • Kidney Tubules, Proximal / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Primary Cell Culture
  • Promoter Regions, Genetic
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptors, Dopamine D2 / genetics*
  • Receptors, Dopamine D2 / metabolism
  • Reperfusion Injury / genetics*
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / pathology
  • Signal Transduction
  • Transfection
  • Wnt3A Protein / genetics*
  • Wnt3A Protein / metabolism
  • beta Catenin / genetics*
  • beta Catenin / metabolism

Substances

  • CTNNB1 protein, mouse
  • DRD2 protein, mouse
  • RNA, Small Interfering
  • Receptors, Dopamine D2
  • Wnt3A Protein
  • Wnt3a protein, mouse
  • beta Catenin