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

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Abstract

Rieger syndrome, an autosomal dominant disorder, includes ocular, craniofacial and umbilical abnormalities. The pitx2 homeobox gene, which is mutated in Rieger syndrome1,2, has been proposed to be the effector molecule interpreting left–right axial information from the early embryonic trunk to each organ3,4,5,6,7. Here we have used gene targeting in mice to generate a loss-of-function allele that would be predicted to result in organ randomization or isomerization. Although pitx2-/- embryos had abnormal cardiac morphogenesis, mutant hearts looped in the normal direction. Pitx2-/- embryos had correctly oriented, but arrested, embryonic rotation and right pulmonary isomerism. They also had defective development of the mandibular and maxillary facial prominences, regression of the stomodeum and arrested tooth development. Fgf8 expression was absent, and Bmp4 expression was expanded in the branchial-arch ectoderm. These data reveal a critical role for pitx2 in left–right asymmetry but indicate that pitx2 may function at an intermediate step in cardiac morphogenesis and embryonic rotation.

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Figure 1: Targeting strategy and cardiac phenotype.
Figure 2: Rotation and pulmonary phenotypes.
Figure 3: Craniofacial phenotype.
Figure 4: Ocular phenotype.

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Acknowledgements

This work was supported by NIH (J.F.M., R.L.J.) and March of Dimes (J.F.M.). We thank J. Smith and M. Cole for help with the manuscript; R. Behringer, S. Potter and C. Tabin for critical comments; B. Hogan, B. Klein, D. Maas, R. Maxson, G. Martin, E. Olson and P. Overbeek for probes; and P. Soriano, R. Behringer, L. Gan and A. Bradley for reagents.

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Authors and Affiliations

  1. Alkek Institute of Biosciences and Technology, Center for Cancer Biology and Nutrition, Texas A&M University System Health Science Center, 2121 Holcombe Blvd, Houston, 77030, Texas, USA

    Mei-Fang Lu, Rex Dyer & James F. Martin

  2. Department of Biochemistry and Molecular Biology, M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, 77030, Texas, USA

    Carolyn Pressman & Randy L. Johnson

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  1. Mei-Fang Lu
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Correspondence to James F. Martin.

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Lu, MF., Pressman, C., Dyer, R. et al. Function of Rieger syndrome gene in left–right asymmetry and craniofacial development. Nature 401, 276–278 (1999). https://doi.org/10.1038/45797

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