Identification of a Wnt/Dvl/beta-Catenin --> Pitx2 pathway mediating cell-type-specific proliferation during development

Cell. 2002 Nov 27;111(5):673-85. doi: 10.1016/s0092-8674(02)01084-x.

Abstract

Understanding the cell type-specific molecular mechanisms by which distinct signaling pathways combinatorially control proliferation during organogenesis is a central issue in development and disease. Here, we report that the bicoid-related transcription factor Pitx2 is rapidly induced by the Wnt/Dvl/beta-catenin pathway and is required for effective cell-type-specific proliferation by directly activating specific growth-regulating genes. Regulated exchange of HDAC1/beta-catenin converts Pitx2 from repressor to activator, analogous to control of TCF/LEF1. Pitx2 then serves as a competence factor required for the temporally ordered and growth factor-dependent recruitment of a series of specific coactivator complexes that prove necessary for Cyclin D2 gene induction. The molecular strategy underlying interactions between the Wnt and growth factor-dependent signaling pathways in cardiac outflow tract and pituitary proliferation is likely to be prototypic of cell-specific proliferation strategies in other tissues.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Cell Division
  • Cell Line
  • Cyclin D2
  • Cyclins / metabolism
  • Cytoskeletal Proteins / metabolism*
  • Dishevelled Proteins
  • Gene Expression Regulation, Developmental
  • Heart / embryology
  • Histone Deacetylases / metabolism
  • Homeodomain Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Biological
  • Nuclear Proteins*
  • Organogenesis / genetics*
  • Phosphoproteins
  • Pituitary Gland / embryology
  • Proteins / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Signal Transduction*
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism*
  • Transcriptional Activation
  • Wnt Proteins
  • Zebrafish Proteins*
  • beta Catenin

Substances

  • Adaptor Proteins, Signal Transducing
  • CTNNB1 protein, mouse
  • Ccnd2 protein, mouse
  • Cyclin D2
  • Cyclins
  • Cytoskeletal Proteins
  • Dishevelled Proteins
  • Homeodomain Proteins
  • Nuclear Proteins
  • Phosphoproteins
  • Proteins
  • Proto-Oncogene Proteins
  • Trans-Activators
  • Transcription Factors
  • Wnt Proteins
  • Zebrafish Proteins
  • beta Catenin
  • homeobox protein PITX2
  • Histone Deacetylases