Self-regulated left-right asymmetric expression of Pitx2c in the developing mouse limb

The transcription factor Pitx2c is expressed in primordial visceral organs in a left-right (L-R) asymmetric manner and executes situs-specific morphogenesis. Here we show that Pitx2c is also L-R asymmetrically expressed in the developing mouse limb. Human PITX2c exhibits the same transcriptional activity in the mouse limb. The asymmetric expression of Pitx2c in the limb also exhibits dorsal-ventral and anterior-posterior polarities, being confined to the posterior-dorsal region of the left limb. Left-sided Pitx2c expression in the limb is regulated by Nodal signaling through a Nodal-responsive enhancer. Pitx2c is expressed in lateral plate mesoderm (LPM)-derived cells in the left limb that contribute to various limb connective tissues. The number of Pitx2c+ cells in the left limb was found to be negatively regulated by Pitx2c itself. Although obvious defects were not apparent in the limb of mice lacking asymmetric Pitx2c expression, Pitx2c may regulate functional L-R asymmetry of the limb.