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:

Loss of the SKI proto-oncogene in individuals affected with 1p36 deletion syndrome is predicted by strain-dependent defects in Ski−/− mice

Abstract

Experiments involving overexpression of Ski have suggested that this gene is involved in neural tube development and muscle differentiation1,2,3,4. In agreement with these findings, Ski−/− mice display a cranial neural tube defect that results in exencephaly and a marked reduction in skeletal muscle mass5. Here we show that the penetrance and expressivity of the phenotype changes when the null mutation is backcrossed into the C57BL6/J background, with the principal change involving a switch from a neural tube defect to midline facial clefting. Other defects, including depressed nasal bridge, eye abnormalities, skeletal muscle defects and digit abnormalities, show increased penetrance in the C57BL6/J background. These phenotypes are interesting because they resemble some of the features observed in individuals diagnosed with 1p36 deletion syndrome, a disorder caused by monosomy of the short arm of human chromosome 1p (refs. 69). These similarities prompted us to re-examine the chromosomal location of human SKI and to determine whether SKI is included in the deletions of 1p36. We found that human SKI is located at distal 1p36.3 and is deleted in all of the individuals tested so far who have this syndrome. Thus, SKI may contribute to some of the phenotypes common in 1p36 deletion syndrome, and particularly to facial clefting.

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: Abnormalities in C57BL/6J, Ski−/− mice.
Figure 2: Human SKI is located on chromosome 1p36.3, proximal to CDC2L1.
Figure 3: SKI is located in the common deleted region in individuals affected with 1p36 syndrome.

Similar content being viewed by others

References

  1. Amaravadi, L.S., Neff, A.W., Sleeman, J.P. & Smith, R.C. Autonomous neural axis formation by ectopic expression of the protooncogene c- ski. Dev. Biol. 192, 392–404 (1997).

    Article  CAS  Google Scholar 

  2. Sutrave, P., Kelly, A.M. & Hughes, S.H. ski can cause selective growth of skeletal muscle in transgenic mice. Genes Dev. 4, 1462–1472 (1990).

    Article  CAS  Google Scholar 

  3. Colmenares, C. & Stavnezer, E. The ski oncogene induces muscle differentiation in quail embryo cells. Cell 59, 293–303 (1989).

    Article  CAS  Google Scholar 

  4. Kaufman, C.D., Martinez-Rodriguez, G. & Hackett, P.B. Ectopic expression of c- ski disrupts gastrulation and neural patterning in zebrafish. Mech. Dev. 95, 147–162 (2000).

    Article  CAS  Google Scholar 

  5. Berk, M., Desai, S.Y., Heyman, H.C. & Colmenares, C. Mice lacking the ski proto-oncogene have defects in neurulation, craniofacial, patterning, and skeletal muscle development. Genes Dev. 11, 2029–2039 (1997).

    Article  CAS  Google Scholar 

  6. Keppler-Noreuil, K.M., Carroll, A.J., Finley, W.H. & Rutledge, S.L. Chromosome 1p terminal deletion: report of new findings and confirmation of two characteristic phenotypes. J. Med. Genet. 32, 619–622 (1995).

    Article  CAS  Google Scholar 

  7. Reish, O., Berry, S.A. & Hirsch, B. Partial monosomy of chromosome 1p36.3: characterization of the critical region and delineation of a syndrome. Am. J. Med. Genet. 59, 467–475 (1995).

    Article  CAS  Google Scholar 

  8. Shapira, S.K. et al. Chromosome 1p36 deletions: the clinical phenotype and molecular characterization of a common newly delineated syndrome. Am. J. Hum. Genet. 61, 642–650 (1997).

    Article  CAS  Google Scholar 

  9. Slavotinek, A., Shaffer, L.G. & Shapira, S.K. Monosomy 1p36. J. Med. Genet. 36, 657–663 (1999).

    CAS  Google Scholar 

  10. Harris, M.J. & Juriloff, D.M. Mini-review: toward understanding mechanisms of genetic neural tube defects in mice. Teratology 60, 292–305 (1999).

    Article  CAS  Google Scholar 

  11. Yao, T.P. et al. Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300. Cell 93, 361–372 (1998).

    Article  CAS  Google Scholar 

  12. McMahon, J.A. et al. Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite. Genes Dev. 12, 1438–1452 (1998).

    Article  CAS  Google Scholar 

  13. Lohnes, D. et al. Function of the retinoic acid receptors (RARs) during development (I). Craniofacial and skeletal abnormalities in RAR double mutants. Development 120, 2738–2748 (1994).

    Google Scholar 

  14. Zhang, J. et al. Neural tube, skeletal and body wall defects in mice lacking transcription factor AP-2. Nature 381, 238–241 (1996).

    Article  CAS  Google Scholar 

  15. Schorle, H., Meier, P., Buchert, M., Jaenisch, R. & Mitchell, P.J. Transcription factor AP-2 essential for cranial closure and craniofacial development. Nature 381, 235–238 (1996).

    Article  CAS  Google Scholar 

  16. Dahl, R., Kieslinger, M., Beug, H. & Hayman, M.J. Transformation of hematopoietic cells by the Ski oncoprotein involves repression of retinoic acid receptor signaling. Proc. Natl Acad. Sci. USA 95, 11187–11192 (1998).

    Article  CAS  Google Scholar 

  17. Luscher, B., Mitchell, P.J., Williams, T. & Tjian, R. Regulation of transcription factor AP-2 by the morphogen retinoic acid and by second messengers. Genes Dev. 3, 1507–1517 (1989).

    Article  CAS  Google Scholar 

  18. Winograd, J. et al. Perinatal lethality and multiple craniofacial malformations in MSX2 transgenic mice. Hum. Mol. Genet. 6, 369–379 (1997).

    Article  CAS  Google Scholar 

  19. Barlow, A.J. & Francis-West, P.H. Ectopic application of recombinant BMP-2 and BMP-4 can change patterning of developing chick facial primordia. Development 124, 391–398 (1997).

    CAS  Google Scholar 

  20. Wang, W., Mariani, F.V., Harland, R.M. & Luo, K. Ski represses bone morphogenic protein signaling in Xenopus and mammalian cells. Proc. Natl Acad. Sci. USA 97, 14394–14399 (2000).

    Article  CAS  Google Scholar 

  21. Wu, Y.Q. et al. Molecular refinement of the 1p36 deletion syndrome reveals size diversity and a preponderance of maternally derived deletions. Hum. Mol. Genet. 8, 313–321 (1999).

    Article  CAS  Google Scholar 

  22. Goodwin, R.G. et al. Molecular cloning and expression of the type 1 and type 2 murine receptors for tumor necrosis factor. Mol. Cell. Biol. 11, 3020–3026 (1991).

    Article  CAS  Google Scholar 

  23. Chaganti, R.S. et al. The cellular homologue of the transforming gene of SKV avian retrovirus maps to human chromosome region 1q22-q24. Cytogenet. Cell Genet. 43, 181–186 (1986).

    Article  CAS  Google Scholar 

  24. Stavnezer, E., Brodeur, D. & Brennan, L.A. The v- ski oncogene encodes a truncated set of c-ski coding exons with limited sequence and structural relatedness to v-myc. Mol. Cell. Biol. 9, 4038–4045 (1989).

    Article  CAS  Google Scholar 

  25. Grimes, H.L., Szente, B.E. & Goodenow, M.M. C- ski cDNAs are encoded by eight exons, six of which are closely linked within the chicken genome. Nucleic Acids Res. 20, 1511–1516 (1992).

    Article  CAS  Google Scholar 

  26. Faivre, L. et al. Prenatal detection of a 1p36 deletion in a fetus with multiple malformations and a review of the literature. Prenat. Diagn. 19, 49–53 (1999).

    Article  CAS  Google Scholar 

  27. Warren, D.S., Morrell, J.C., Moser, H.W., Valle, D. & Gould, S.J. Identification of PEX10, the gene defective in complementation group 7 of the peroxisome-biogenesis disorders. Am. J. Hum. Genet. 63, 347–359 (1998).

    Article  CAS  Google Scholar 

  28. Gould, S.J. & Valle, D. Peroxisome biogenesis disorders: genetics and cell biology. Trends Genet. 16, 340–345 (2000).

    Article  CAS  Google Scholar 

  29. Pinkel, D., Straume, T. & Gray, J.W. Cytogenetic analysis using quantitative, high-sensitivity, fluorescence hybridization. Proc. Natl Acad. Sci. USA 83, 2934–2938 (1986).

    Article  CAS  Google Scholar 

  30. Shaffer, L.G. et al. Molecular characterization of de novo secondary trisomy 13. Am. J. Hum. Genet. 55, 968–974 (1994).

    CAS  Google Scholar 

Download references

Acknowledgements

This work was funded by grants from the NIH (to C.C., H.H., S.S., J.M. and E.S.). We thank P. Klepcyk, N. Lerner, B. Ludwig and W. Matheny for technical assistance and A. Lidral and J. Nadeau for insightful suggestions.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Clemencia Colmenares.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Colmenares, C., Heilstedt, H., Shaffer, L. et al. Loss of the SKI proto-oncogene in individuals affected with 1p36 deletion syndrome is predicted by strain-dependent defects in Ski−/− mice. Nat Genet 30, 106–109 (2002). https://doi.org/10.1038/ng770

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng770

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