Dosage requirement of Pitx2 for development of multiple organs

Pitx2 is a homeodomain transcription factor that is mutated in Rieger syndr ome, a haploinsufficiency disorder affecting eyes and teeth. Pitx2 also has a postulated role in left-right axis determination. We assessed the requir ements for Pitx2 directly by generating hypomorphic and null alleles, Heter ozygotes for either allele have eye abnormalities consistent with Rieger sy ndrome. The ventral body wall fails to close in embryos homozygous for the null allele, leaving the heart and abdominal organs externalized and the bo dy axis contorted. In homozygotes for either allele, the heart tube undergo es normal, rightward looping and the stomach is positioned normally. In con trast, homozygotes for both alleles exhibit right isomerization of the lung s. Thus, Pitx2 is required for left-right asymmetry of the lungs but not ot her organs, Homozygotes for either allele exhibit septal and valve defects, and null homozygotes have a single atrium proving that a threshold level o f Pitx2 is required for normal heart development. Null homozygotes exhibit arrest of pituitary gland development at the committed Rathke pouch stage a nd eye defects including optic nerve coloboma and absence of ocular muscles . This allelic series establishes that Pitx2 is required for the developmen t of mulitple organs in a dosage-sensitive manner.