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:

SOX10 mutation disrupts neural crest development in Dom Hirschsprung mouse model

Nature Genetics volume 18, pages 60–64 (1998)Cite this article

Abstract

Hirschsprung disease (HSCR, MIM ♯142623) is a multigenic neuocristopathy (neural crest disorder) characterized by absence of enteric ganglia in a variable portion of the distal colon. Subsets of HSCR individuals also present with neural crest-derived melanocyte deficiencies (Hirschsprung-Waardenburg, HSCR-WS, MIM ♯277580). Murine models have been instrumental in the identification and analysis of HSCR disease genes. These include mice with deficiencies of endothelin B receptor (Ednrbs–l refs 1,2) endothelin 3 (Edn3ls; refs 1,3) the tyrosine kinase receptor cftet4 and glial-derived neurotrophic factor5–7. Another mouse model of HSCR disease, Dom, arose spontaneously at the Jackson Laboratory8. While Dom/+ heterozygous mice display regional deficiencies of neural crest–derived enteric ganglia in the distal colon, Dom/Dom homozygous animals are embryonic lethal8. We have determined that premature termination of SOX10, a member of the SflV–like HMG box family of transcription factors, is responsible for absence of the neural crest derivatives in Dom mice. We demonstrate expression of SOX10 in normal neural crest cells, disrupted expression of both SOX10 and the HSCR disease gene Ednrb in Dom mutant embryos, and loss of neural crest derivatives due to apoptosis. Our studies suggest that SOX10 is essential for proper peripheral nervous system development. We propose SOX10 as a candidate disease gene for individuals with HSCR whose disease does not have an identified genetic origin.

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

Similar content being viewed by others

References

  1. Lane, P.W. Association of megacolon with two recessive spotting genes in the mouse. J. Hered. 57, 29–31 (1966).

    Article  CAS  Google Scholar 

  2. Hosoda, K. et al. Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice. Cell 79, 1267–1276 (1994)

    Article  CAS  Google Scholar 

  3. Baynash, A.G. et al. Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell 79, 1277–1285 (1994).

    Article  CAS  Google Scholar 

  4. Schuchardt, A., D'Agati, V., Larsson-Blomberg, L., Costantini, F. & Pachnis, V. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 367, 380–383 (1994).

    Article  CAS  Google Scholar 

  5. Sanchez, M.P. et al. Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 382, 70–73 (1996).

    Article  CAS  Google Scholar 

  6. Pichel, J.G. et al. Defects in enteric innervation and kidney development in mice lacking GDNF. Nature 382, 73–76 (1996).

    Article  CAS  Google Scholar 

  7. Moore, M.W. et al. Renal and neuronal abnormalities in mice lacking GDNF. Nature 382, 76–79 (1996).

    Article  CAS  Google Scholar 

  8. Lane, P.W. & Liu, H.M. Association of megacolon with a new dominant spotting gene (Dom) in the mouse. J. Hered. 75, 435–439 (1984).

    Article  CAS  Google Scholar 

  9. Pingault, V. et al. Human homology and candidate genes for the Dominant megacolon locus, a mouse model of Hirschsprung disease. Genomics 39, 86–89 (1997).

    Article  CAS  Google Scholar 

  10. Puliti, A. et al. A high-resolution genetic map of mouse chromosome 15 encompassing the Dominant megacolon (Dom) locus. Mamm. Genome 6, 763–768 (1995).

    Article  CAS  Google Scholar 

  11. Stock, D.W., Buchanan, A.V., Zhao, Z. & Weiss, K.M. Numerous members of the Sox family of HMG box-containing genes are expressed in developing mouse teeth. Genomics 37, 234–237 (1996).

    Article  CAS  Google Scholar 

  12. Wright, E.M., Snopek, B. & Koopman, P. Seven new memebers of the Sox gene family of HMG box-containing genes are expressed during mouse development Nucleic Acids Res. 21, 744 (1993).

    Article  CAS  Google Scholar 

  13. Tani, M. et al. Isolation of a novel Sry-related gene that is expressed in high-metastatic K-1735 murine melanoma cells. Genomics 39, 30–37 (1997).

    Article  CAS  Google Scholar 

  14. Hashimoto, Y. et al. Identification of genes differentially expressed in association with metastatic potential of K-1735 murine melanoma by messenger RNA differential display. Cancer Res. 56, 5266–5271 (1996).

    CAS  PubMed  Google Scholar 

  15. Bennett, D.C., Cooper, P.J. & Hart, I.R. A line of non-tumorigenic mouse melanocytes, syngeneic with the B16 melanoma and requiring a tumour promoter for growth. Int. J. Cancer 39, 414–418 (1987).

    Article  CAS  Google Scholar 

  16. Gershon, M.D. Neural crest development: do developing enteric neurons need endothelins? Curr. Biol. 5, 601–604 (1995).

    Article  CAS  Google Scholar 

  17. Kapur, R.P., Sweetser, D.A., Doggett, B., Siebert, J.R. & Palmiter, R.D. Intercellular signals downstream of endothelin receptor-B mediate colonization of the large intestine by enteric neuroblasts. Development 121, 3787–3795 (1995).

    CAS  PubMed  Google Scholar 

  18. Lahav, R., Ziller, C, Dupin, E. & Le Douarin, N.M. Endothelin 3 promotes neural crest cell proliferation and mediates a vast increase in melanocyte number in culture. Proc. atal. Acad. Sci. USA 93, 3892–3897 (1996).

    Article  CAS  Google Scholar 

  19. Opdecamp, K. et al. Melanocyte development in vivo and in neural crest cel cultures: crucial dependence on the Mitf basic-helix-loop-helix-zipper transcription factor. Development 124, 2377–2386 (1997).

    CAS  PubMed  Google Scholar 

  20. Reid, K. et al. Multiple roles for endothelin in melanocyte development: regulation of progenitor number and stimulation of differentiation. Development 122, 3911–3919 (1996).

    CAS  PubMed  Google Scholar 

  21. Steel, K.P., Davidson, D.R. & Jackson, I.J. TRP-2/DT, a new early melanoblast marker, shows that steel growth factor (c-kit ligand) is a survival factor. Development 115, 1111–1119 (1992).

    CAS  PubMed  Google Scholar 

  22. Pavan, W.J. & Tilghman, S.M. Piebald lethal (s1) acts early to disrupt the development of neural crest-derived melanocytes. Proc. Natl. Acad. Sci. USA 91, 7159–7163 (1994).

    Article  CAS  Google Scholar 

  23. Pevny, L.H. & Lovell-Badge, R. Sox genes find their feet. Curr. Opin. Genet. Dev. 7, 338–344 (1997).

    Article  CAS  Google Scholar 

  24. Prior, H.M. & Walter, M.A. SOX genes: architects of development. Mol. Med. 2, 405–412 (1996).

    Article  CAS  Google Scholar 

  25. Foster, J.W. et al. Campomelic dysplasia and autosomal sex reversal caused by mutations in an SKV-related gene. Nature 372, 525–530 (1994).

    Article  CAS  Google Scholar 

  26. Schilham, M.W., Moerer, P., Cumano, A. & Clevers, H.C. Sox-4 facilitates thymocyte differentiation. Eur. J. Immunol. 27, 1292–1295 (1997).

    Article  CAS  Google Scholar 

  27. Wagner, T. et al. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell 79, 1111–1120 (1994).

    Article  CAS  Google Scholar 

  28. Bell, D.M. et al. SOX9 directly regulates the type-ll collagen gene. Nature Genet. 16, 174–178 (1997).

    Article  CAS  Google Scholar 

  29. Sudbeck, P., Schmitz, M.L., Baeuerle, P.A. & Scherer, G. Sex reversal by loss of the C-terminal transactivation domain of human SOX9. Nature Genet. 13, 230–232 (1996).

    Article  CAS  Google Scholar 

  30. Kapur, R.P. et al. Abnormal microenvironmental signals underlie intestinal aganglionosis in Dominant megacolon mutant mice. Dev. Biol. 174, 360–369 (1996).

    Article  CAS  Google Scholar 

  31. Kapur, R.P., Yost, C. & Palmiter, R.D. Aggregation chimeras demonstrate that the primary defect responsible for aganglionic megacolon in lethal spotted mice is not neuroblast autonomous. Development 117, 993–999 (1993).

    CAS  PubMed  Google Scholar 

  32. Rothman, T.P., Goldowitz, D. & Gershon, M.D. Inhibition of migration of neural crest-derived cells by the abnormal mesenchyme of the presumptive aganglionic bowel of Is/Is mice: analysis with aggregation and interspecies chimeras. Dev. Biol. 159, 559–573 (1993).

    Article  CAS  Google Scholar 

  33. Dudov, K.P. & Perry, R.P. The gene family encoding the mouse ribosomal protein L32 contains a uniquely expressed intron-containing gene and an unmutated processed gene. Cell 37, 457–468 (1984).

    Article  CAS  Google Scholar 

  34. Pavan, W.J., Mac, S., Cheng, M. & Tilghman, S.M. Quantitative trait loci that modify the severity of spotting in piebald mice. Genome Res. 5, 29–41 (1995).

    Article  CAS  Google Scholar 

  35. Swift, G.H., Dagorn, J.C., Ashley, P.L, Cummings, S.W. & MacDonald, R.J. Rat pancreatic kallikrein mRNA: nucleotide sequence and amino acid sequence of the encoded preproenzyme. Proc. Natl. Acad. Sci. USA 79, 7263–7267 (1982).

    Article  CAS  Google Scholar 

  36. Wilkinson, D.G. & Nieto, M.A. Detection of messenger RNA by in situ hybridization to tissue sections and whole mounts. Methods Enzymol. 225, 361–373 (1993).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Mouse Embryology Section, Building 49, Room 4A82, Laboratory of Genetic Disease Research, National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive MSC 4472, Bethesda, Maryland, 20892-4472, USA

    E. Michelle Southard-Smith, Lidia Kos & William J Pavan

Authors
  1. E. Michelle Southard-Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lidia Kos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. William J Pavan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William J Pavan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Southard-Smith, E., Kos, L. & Pavan, W. SOX10 mutation disrupts neural crest development in Dom Hirschsprung mouse model. Nat Genet 18, 60–64 (1998). https://doi.org/10.1038/ng0198-60

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0198-60

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