title: The Pitx2c N-terminal domain is a critical interaction domain required for asymmetric morphogenesis.
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.
authors.affiliation: The Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.
authors.forename: Annie
authors.initials: A
authors.lastname: Simard
authors.forename: Luciano
authors.initials: L
authors.lastname: Di Giorgio
authors.forename: Melanie
authors.initials: M
authors.lastname: Amen
authors.forename: Ashley
authors.initials: A
authors.lastname: Westwood
authors.forename: Brad A
authors.initials: BA
authors.lastname: Amendt
authors.forename: Aimee K
authors.initials: AK
authors.lastname: Ryan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D002478:Cells, Cultured; D002642:Chick Embryo; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000033:anatomy & histology / Q000196:embryology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007930:Leucine / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000097577:Homeobox Protein PITX2
chemical_list: D018398:Homeodomain Proteins; D007930:Leucine; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; D020033:Protein Isoforms; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2
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