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.

  • Article
  • Published:

DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1

Nature Genetics volume 27, pages 286–291 (2001)Cite this article

Abstract

The DiGeorge/velocardiofacial syndrome (DGS/VCFS) is a relatively common human disorder, usually associated with deletions of chromosome 22q11. The genetic basis for the wide range of developmental anomalies in the heart, glands and facial structures has been elusive. We have investigated the potential role of one candidate gene, Tbx1, which encodes a transcription factor of the T-box family, by producing a null mutation in mice. We found that mice heterozygous for the mutation had a high incidence of cardiac outflow tract anomalies, thus modeling one of the major abnormalities of the human syndrome. Moreover, Tbx1−/− mice displayed a wide range of developmental anomalies encompassing almost all of the common DGS/VCFS features, including hypoplasia of the thymus and parathyroid glands, cardiac outflow tract abnormalities, abnormal facial structures, abnormal vertebrae and cleft palate. On the basis of this phenotype in mice, we propose that TBX1 in humans is a key gene in the etiology of DGS/VCFS.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Targeting of Tbx1 by homologous recombination to produce the null Tbx1tm1Pa allele.
Figure 2: Tbx1 wild-type and homozygous mutant neonates.
Figure 3: Whole mounts of wild-type (+/+) and Tbx1 homozygous mutant (−/−) embryos at E9.5.
Figure 4: Histology of wild-type and homozygous mutant embryos.
Figure 5: Cartilage preparations of wild-type (+/+) and mutant (−/−) E14.5 embryos.
Figure 6: Skeletal staining of wild-type (+/+), heterozygous (+/−) and homozygous mutant (−/−) fetuses at E17.5 showing ossified areas in red and cartilage in blue.
Figure 7: E11.5 embryos following the injection of India ink into the left ventricle.

Similar content being viewed by others

References

  1. Scambler, P.J. The 22q11 deletion syndromes. Hum. Mol. Genet. 9, 2421–2426 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Goldberg, R., Motzkin, B., Marion, R., Scambler, P.J. & Shprintzen, R.J. Velo-cardio-facial syndrome: a review of 120 patients. Am. J. Hum. Genet. 45, 313–319 (1993).

    Article  CAS  Google Scholar 

  3. McLean, S.D., Saal, H.M., Spinner, N.B., Emanuel, B.S. & Driscoll, D.A. Velo-cardio-facial syndrome. Intrafamilial variability of the phenotype. Am. J. Dis. Child. 147, 1212–1216 (1993).

    Article  CAS  PubMed  Google Scholar 

  4. Goodship, J., Cross, I., Scambler, P. & Burn, J. Monozygotic twins with chromosome 22q11 deletion and discordant phenotype. J. Med. Genet. 32, 746–748 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. McDonald-McGinn, D.M. et al. The 22q11.2 deletion: screening, diagnostic workup, and outcome of results; report on 181 patients. Genetic Testing 1, 99–108 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Gogos, J.A. et al. Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc. Natl. Acad. Sci. USA 95, 9991–9996 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kimber, W.L. et al. Deletion of 150 kb in the minimal DiGeorge/velocardiofacial syndrome critical region in mouse. Hum. Mol. Genet. 8, 2229–2237 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Lindsay, E.A. et al. Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature 401, 379–383 (1999).

    CAS  PubMed  Google Scholar 

  9. Puech, A. et al. Normal cardiovascular development in mice deficient for 16 genes in 550 kb of the velocardiofacial/DiGeorge syndrome region. Proc. Natl. Acad. Sci. USA 97, 10090–10095 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Saint-Jore, B. et al. Goosecoid-like (Gscl), a candidate gene for velocardiofacial syndrome, is not essential for normal mouse development. Hum. Mol. Genet. 7, 1841–1849 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Wakamiya, M., Lindsay, E.A., Rivera-Perez, J.A., Baldini, A. & Behringer, R.R. Functional analysis of Gscl in the pathogenesis of the DiGeorge and velocardiofacial syndromes. Hum. Mol. Genet. 7, 1835–1840 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Chieffo, C. et al. Isolation and characterization of a gene from the DiGeorge chromosomal region (DGCR) homologous to the mouse Tbx1 gene. Genomics 43, 267–277 (1997).

    Article  CAS  PubMed  Google Scholar 

  13. Bollag, R.J. et al. An ancient family of embryonically expressed mouse genes sharing a conserved protein motif with the T locus. Nature Genet. 7, 383–389 (1994).

    Article  CAS  PubMed  Google Scholar 

  14. Chapman, D.L. et al. Expression of the T-box family genes, Tbx1–Tbx5, during early mouse development. Dev. Dyn. 206, 379–390 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Epstein, J.A. et al. Migration of cardiac neural crest cells in Splotch embryos. Development 127, 1869–1878 (2000).

    CAS  PubMed  Google Scholar 

  16. Dahl, E., Kosedi, H. & Balling, R. Pax genes and organogenesis. Bioessays 19, 755–765 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Stockton, D.W., Das, P., Goldenberg, M., D'Souza, R.M. & Patel, P.I. Mutation of PAX9 is associated with oligodontia. Nature Genet. 24, 18–19 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Peters, H., Neubuser, A., Kratochwil, K. & Balling, R. Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities. Genes Dev. 12, 2735–2747 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Satokata, I. et al. Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation. Nature Genet. 24, 391–395 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Wilkie, A.O.M. et al. Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification. Nature Genet. 24, 387–390 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Wilming, L.G., Snoeren, C.A.S., van Rijswijk, A., Grosveld, F. & Meijers, C. The murine homologue of HIRA, a DiGeorge syndrome candidate gene, is expressed in embryonic structures affected in human CATCH22 patients. Hum. Mol. Genet. 6, 247–258 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Roberts, C., Daw, S.C.M., Halford, S. & Scambler, P.J. Cloning and developmental expression analysis of chick Hira (Chira), a candidate gene for DiGeorge syndrome. Hum. Mol. Genet. 6, 237–245 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Farrell, M.J. et al. HIRA, a DiGeorge syndrome candidate gene, is required for cardiac outflow tract septation. Circ. Res. 84, 127–135 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Wakamiya, M., Rivera-Perez, J.A., Baldini, A. & Behringer, R.R. Goosecoid and Goosecoid-related genes in mouse embryogenesis. Cold Spring Harb. Symp. Quant. Biol. 62, 145–149 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Yamagishi, H., Garg, V., Matsuoka, R., Thomas, T. & Srivastava, D. A molecular pathway revealing a genetic basis for human cardiac and craniofacial defects. Science 283, 1158–1161 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Nagy, A., Rossant, J., Nagy, R., Abramow-Newerly, W. & Roder, J. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc. Natl. Acad. Sci. USA 90, 8424–8428 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hogan, B., Beddington, R., Costantini, F. & Lacy, E. (eds.) Manipulating the Mouse Embryo. A Laboratory Manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1994).

    Google Scholar 

  28. Mallo, M. & Brändlin, I. Segmental identity can change independently in the hindbrain and rhombencephalic neural crest. Dev. Dyn. 210, 146–156 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Wilkinson, D.G. Whole Mount In Situ Hybridization of Vertebrate Embryos (IRL Press, Oxford, 1992).

    Google Scholar 

Download references

Acknowledgements

We thank D. Chapman, J.J. Gibson-Brown, T. Davenport, S. Hancock, N. Adler, K. Hadjantonakis and L. Silver and members of his laboratory for support and helpful criticism; J. Colgan for help with the T-cell analysis; N. Manley for probes; T. Bestor and M. Budarf for critical reading of the manuscript; and M. Bucan for first pointing out that the position of Tbx1 is in a region syntenic to 22q11. This work was supported by NIH grant HD33082 and the Raymond and Beverley Sackler Foundation. L.A.J. was supported by a National Science Foundation predoctoral fellowship.

Author information

Authors and Affiliations

  1. Department of Genetics and Development, College of Physicians and Surgeons of Columbia University, New York, New York, USA

    Loydie A. Jerome & Virginia E. Papaioannou

Authors
  1. Loydie A. Jerome
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Virginia E. Papaioannou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Virginia E. Papaioannou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jerome, L., Papaioannou, V. DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat Genet 27, 286–291 (2001). https://doi.org/10.1038/85845

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/85845

This article is cited by

Search

Advanced 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