The Pitx2c N-terminal domain is a critical interaction domain required for asymmetric morphogenesis

Dev Dyn. 2009 Oct;238(10):2459-70. doi: 10.1002/dvdy.22062.

Abstract

The paired-like homeodomain transcription factor Pitx2c has an essential role in patterning the left-right axis. However, neither its transcriptional targets nor the molecular mechanisms through which it exerts its patterning function are known. Here we provide evidence that the N-terminal domain of Pitx2c is important for this activity. Overexpression of the Pitx2c N-terminus in ovo randomizes the direction of heart looping, the first morphological asymmetry conserved in vertebrate embryos. In addition, the Pitx2c N-terminal domain blocks the ability of Pitx2c to synergize with Nkx2.5 to transactivate the procollagen lysyl hydroxylase (Plod-1) promoter in transient transfection assays. A five amino acid region containing leucine-41 is required for both of these effects. Our data suggest that the Pitx2c N-terminal domain competes with endogenous Pitx2c for binding to a protein interaction partner that is required for the activation of genes that direct asymmetric morphogenesis along the left-right axis.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Body Patterning / physiology*
  • Cells, Cultured
  • Chick Embryo
  • Gene Expression Regulation, Developmental
  • Heart / anatomy & histology
  • Heart / embryology*
  • Homeobox Protein PITX2
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Leucine / metabolism
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / genetics
  • Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / metabolism
  • Promoter Regions, Genetic
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism*
  • Sequence Alignment
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptional Activation

Substances

  • Homeodomain Proteins
  • Protein Isoforms
  • Transcription Factors
  • Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase
  • Leucine