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

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. Developmental Dynamics 238:2459–2470, 2009. © 2009 Wiley‐Liss, Inc.