Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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

Similar content being viewed by others

References

  1. Semina,E. V. et al. Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nature Genet. 14, 392–399 (1996).

    Article  CAS  Google Scholar 

  2. Gage,P. J. & Camper,S. A. Pituitary homeobox 2, a novel member of the bicoid-related family of homeobox genes, is a potential regulator of anterior structure formation. Hum. Mol. Genet. 6, 457–464 (1997).

    Article  CAS  Google Scholar 

  3. Logan,M., Pagan-Westphal,S. M., Smith,D. M., Paganessi,L. & Tabin,C. J. The transcription factor Pitx2 mediates situs-specific morphogenesis in response to left-right asymmetric signals. Cell 94, 307–317 (1998).

    Article  CAS  Google Scholar 

  4. Piedra,M. E., Icardo,J. M., Albajar,M., Rodriguez-Rey,J. C. & Ros,M. A. Pitx2 participates in the late phase of the pathway controlling left-right asymmetry. Cell 94, 319–324 (1998).

    Article  CAS  Google Scholar 

  5. Yoshioka,H. et al. Pitx2, a bicoid-type homeobox gene, is involved in a lefty-signaling pathway in determination of left-right asymmetry. Cell 94, 299–305 (1998).

    Article  CAS  Google Scholar 

  6. Ryan,A. K. et al. Pitx2 determines left-right asymmetry of internal organs in vertebrates. Nature 394, 545–551 (1998).

    Article  ADS  CAS  Google Scholar 

  7. Campione,M. et al. The homeobox gene Pitx2: mediator of asymmetric left-right signaling in vertebrate heart and gut looping. Development 126, 1225–1234 (1999).

    CAS  PubMed  Google Scholar 

  8. Flomen,R. H. et al. Construction and analysis of a sequence-ready map in 4q25: Rieger syndrome can be caused by haploinsufficiency of RIEG, but also by chromosome breaks approximately 90 kb upstream of this gene. Genomics 47, 409–413 (1998).

    Article  CAS  Google Scholar 

  9. Harvey,R. P. Links in the left/right axial pathway. Cell 94, 273–276 (1998).

    Article  CAS  Google Scholar 

  10. Yost,H. J. Vertebrate left-right development. Cell 82, 689–692 (1995).

    Article  CAS  Google Scholar 

  11. Biben,C. & Harvey,R. P. Homeodomain factor Nkx2-5 controls left/right asymmetric expression of bHLH gene eHand during murine heart development. Genes Dev. 11, 1357–1369 (1997).

    Article  CAS  Google Scholar 

  12. Kaufman,M. H. The Atlas of Mouse Development (Academic, London, San Diego, New York, 1992).

    Google Scholar 

  13. Mikkila,S. P., Janas,M., Karikoski,R., Tarkkila,T. & Simola,K. O. X-linked laterality sequence in a family with carrier manifestations. Am. J. med. Genet. 49, 435–438 (1994).

    Article  CAS  Google Scholar 

  14. Gebbia,M. et al. X-linked situs abnormalities result from mutations in ZIC3. Nature Genet. 17, 305–308 (1997).

    Article  CAS  Google Scholar 

  15. Oh,S. P. & Li,E. The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse. Genes Dev. 11, 1812–1826 (1997).

    Article  CAS  Google Scholar 

  16. Neubuser,A., Peters,H., Balling,R. & Martin,G. R. Antagonistic interactions between FGF and BMP signaling pathways: a mechanism for positioning the sites of tooth formation. Cell 90, 247–255 (1997).

    Article  CAS  Google Scholar 

  17. Vainio,S., Karavanova,I., Jowett,A. & Thesleff,I. Identification of BMP-4 as a signal mediating secondary induction between epithelial and mesenchymal tissues during early tooth development. Cell 75, 45–58 (1993).

    Article  CAS  Google Scholar 

  18. Johnston,M. C., Noden,D. M., Hazelton,R. D., Coulombre,J. L. & Coulombre,A. J. Origins of avian ocular and periocular tissues. Exp. Eye Res. 29, 27–43 (1979).

    Article  CAS  Google Scholar 

  19. Meno,C. et al. lefty-1 is required for left-right determination as a regulator of lefty-2 and nodal. Cell 94, 287–297 (1998).

    Article  CAS  Google Scholar 

  20. Lu,M. F. et al. prx-1 functions cooperatively with another paired-related homeobox gene, prx-2, to maintain cell fates within the craniofacial mesenchyme. Development 126, 495–504 (1999).

    CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to James F. Martin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/45797

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing