Tbx5 and Tbx4 transcription factors interact with a new chicken PDZ-LIM protein in limb and heart development

Ange Krause, William Zacharias, Troy Camarata, Barbara Linkhart, Evelyn Law, Antje Lischke, Erik Miljan, Hans Georg Simon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

The T-domain transcription factors, Tbx5 and Tbx4, play important roles in vertebrate limb and heart development. To identify interacting and potential Tbx-regulating proteins, we performed a yeast two-hybrid screen with the C-terminal domain of Tbx5 as bait. We identified a new PDZ-LIM protein composed of one N-terminal PDZ and three C-terminal LIM domains, which we named chicken LMP-4. Among the Tbx2, 3, 4, 5 subfamily, we observed exclusive interaction with Tbx5 and Tbx4 proteins. Tbx3 nor Tbx2 can substitute for LMP-4 binding. While chicken LMP-4 associates with Tbx5 or Tbx4, it uses distinct LIM domains to bind to the individual proteins. Subcellular co-localization of LMP-4 and Tbx proteins supports the protein interaction and reveals interference of LMP-4 with Tbx protein distribution, tethering the transcription factors to the cytoskeleton. The protein-protein interaction indicates regulation of Tbx function at the level of transcription factor nuclear localization. During chicken limb and heart development, Tbx5/LMP-4 and Tbx4/LMP-4 are tightly co-expressed in a temporal and spatial manner, suggesting that they operate in the same pathway. Surprisingly, chicken LMP-4 expression domains outside those of Tbx5 in the heart led to the discovery of Tbx4 expression in the outflow tract and the right ventricle of this organ. The Tbx4-expressing cells coincide with those of the recently discovered secondary anterior heart-forming field. The discrete posterior or anterior expression domains in the heart and the exclusive fore- or hindlimb expression of Tbx5 and Tbx4, respectively, suggest common pathways in the heart and limbs. The identification of a new Tbx5/4-specific binding factor further suggests a novel mechanism for Tbx transcription factor regulation in development and disease.

Original languageEnglish (US)
Pages (from-to)106-120
Number of pages15
JournalDevelopmental Biology
Volume273
Issue number1
DOIs
StatePublished - Sep 1 2004

Keywords

  • Cardiac development
  • GST co-precipitation
  • In situ hybridization
  • LMP-4
  • Limb development
  • Pattern formation
  • Protein interaction
  • Tbx4
  • Tbx5
  • Yeast two-hybrid

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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