Function of Rieger syndrome gene in left-right asymmetry and craniofacial development

Rieger syndrome, an autosomal dominant disorder, includes ocular, craniofac ial and umbilical abnormalities, The pitx2 homeobox gene, which is mutated in Rieger syndrome(1,2), has been proposed to be the effector molecule inte rpreting left-right axial information from the early embryonic trunk to eac h organ(3-7). Here we have used gene targeting in mice to generate a loss-o f-function allele that would be predicted to result in organ randomization or isomerization. Although pitx2(-/-) embryos had abnormal cardiac morphoge nesis, mutant hearts looped in the normal direction. Pitx2(-/-) embryos had correctly oriented, but arrested, embryonic rotation and right pulmonary i somerism. They also had defective development of the mandibular and maxilla ry facial prominences, regression of the stomodeum and arrested tooth devel opment. Fgf8 expression was absent, and Bmp4 expression was expanded in the branchial-arch ectoderm. These data reveal a critical role for pitx2 in le ft-right asymmetry but indicate that pitx2 may function at an intermediate step in cardiac morphogenesis and embryonic rotation.