Pitx2

Pitx2 is a vertebrate transcription factor encoded by the PITX2 gene. It belongs to the homeobox-containing bicoid-class family and acts as a DNA-binding protein that regulates the expression of downstream genes during embryonic development. The gene produces several protein isoforms, primarily through alternative promoter usage and splicing; these isoforms (such as PITX2A, PITX2B, and PITX2C) share the conserved homeodomain but differ in their N-terminal regions, enabling tissue-specific regulation.

Expression and function: PITX2 is active in craniofacial mesenchyme, developing eyes, the heart, and the left-right organizer of the embryo. In vertebrates, PITX2 is crucial for establishing left-right asymmetry, becoming enriched on the left side of the lateral plate mesoderm downstream of Nodal signaling and directing left-sided morphogenesis. In the heart, Pitx2 influences atrial identity and chamber morphogenesis and contributes to outflow tract development and septation. In the craniofacial region, Pitx2 regulates tooth and facial development, and in the eye it participates in anterior segment formation.

Clinical significance: Heterozygous mutations or haploinsufficiency of PITX2 cause Axenfeld-Rieger syndrome, a form of anterior segment dysgenesis associated with iris and corneal abnormalities and an increased risk of glaucoma. Dental and facial anomalies are also common. Because of its central role in left-right patterning and organogenesis, PITX2 mutations can be linked to a range of ocular, cardiac, and visceral malformations in humans and model organisms.