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Phenotype of mice lacking functional Deleted in colorectal cancer (Dec) gene

Nature volume 386, pages 796–804 (1997)Cite this article

Abstract

The DCC (Deleted in colorectal cancer) gene was first identified as a candidate for a tumour-suppressor gene on human chromosome 18q. More recently, in vitro studies in rodents have provided evidence that DCC might function as a receptor for the axonal chemoattractant netrin-1. Inactivation of the murine Dcc gene caused defects in axonal projections that are similar to those observed in netrin-1-deficient mice but did not affect growth, differentiation, morphogenesis or tumorigenesis in mouse intestine. These observations fail to support a tumour-suppressor function for Dcc, but are consistent with the hypothesis that DCC is a component of a receptor for netrin-1.

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References

  1. Fearon, E. R. et al. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science 247, 49–56 (1990).

    Article  ADS  CAS  Google Scholar 

  2. Cavenee, W. K. et al. Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305, 779–784 (1983).

    Article  ADS  CAS  Google Scholar 

  3. Boland, C. R., Sato, J., Appelman, H. D., Bresalier, R. S. & Feinberg, A. P. Microallelotyping defines the sequence and tempo of allelic losses at tumour suppressor gene loci during colorectal cancer progression. Nature Med. 1, 902–909 (1995).

    Article  CAS  Google Scholar 

  4. Vogelstein, B. et al. Genetic alterations during colorectal-tumor development. N. Engl. J. Med. 319, 525–532 (1988).

    Article  CAS  Google Scholar 

  5. Tanaka, K. et al. Suppression of tumorigenicity in human colon carcinoma cells by introduction of normal chromosome 5 or 18. Nature 349, 340–342 (1991).

    Article  ADS  CAS  Google Scholar 

  6. Goyette, M. C. et al. Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect via chromosome transfer. Mol. Cell. Biol. 12, 1387–1395 (1992).

    Article  CAS  Google Scholar 

  7. Cho, K. R. et al. The DCC gene: structural analysis and mutations in colorectal carcinomas. Genomics 19, 525–531 (1994).

    Article  CAS  Google Scholar 

  8. Kikuchi-Yanoshita, R., Konishi, M., Fukunari, H., Tanaka, K. & Miyaki, M. Loss of expression of the DCC gene during progression of colorectal carcinomas in familial adenomatous polyposis and non-familial adenomatous polyposis patients. Cancer Res. 52, 3801–3803 (1992).

    CAS  PubMed  Google Scholar 

  9. Thiagalingam, S. et al. Evaluation of candidate tumor suppressor genes on chromosome 18 in colorectal cancers. Nature Genet. 13, 343–346 (1996).

    Article  CAS  Google Scholar 

  10. Narayanan, R. et al. Antisense RNA to the putative tumor-suppressor gene DCC transforms Rat-1 fibroblasts. Oncogene 7, 553–561 (1992).

    CAS  PubMed  Google Scholar 

  11. Klingelhutz, A. J., Hedrick, L., Cho, K. R. & McDougall, J. K. The DCC gene suppresses the malignant phenotype of transformed human epithelial cells. Oncogene 10, 1581–1586 (1995).

    CAS  PubMed  Google Scholar 

  12. Keino-Masu, K. et al. Deleted in colon cancer (DCC) encodes a netrin receptor. Cell 87, 175–185 (1996).

    Article  CAS  Google Scholar 

  13. Tessier-Lavigne, M., Placzek, M., Lumsden, A. G. S., Dodd, J. & Jessell, T. M. Chemotropic guidance of developing axons in the mammalian central nervous system. Nature 336, 775–778 (1988).

    Article  ADS  CAS  Google Scholar 

  14. Placzek, M., Tessier-Lavigne, M., Jessell, T. M. & Dodd, J. Orientation of commissural axons in vitro in response to a floor plate-derived chemoattractant. Development 110, 19–30 (1990).

    CAS  Google Scholar 

  15. Serafini, T. et al. The netrins define a family of axon outgrowth-promoting proteins homologous to C. elegans UNC-6. Cell 78, 409–424 (1994).

    Article  CAS  Google Scholar 

  16. Kennedy, T. E., Serafini, T., de la Torre, J. R. & Tessier-Lavigne, M. Netrins are diffusible chemotropic factors for commissural axons in the embryonic spinal cord. Cell 78, 425–435 (1994).

    Article  CAS  Google Scholar 

  17. Serafini, T. et al. Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell 87, 1001–1014 (1996).

    Article  CAS  Google Scholar 

  18. Ishii, N., Wadsworth, W. G., Stern, B. D., Culotti, J. G. & Hedgecock, E. M. UNC-6, a laminin-related protein, guides cell and pioneer axon migrations in C. elegans. Neuron 9, 873–881 (1992).

    Article  CAS  Google Scholar 

  19. Wadsworth, W. G., Bhatt, H. & Hedgecock, E. M. Neuroglia and pioneer neurons express UNC-6 to provide global and local netrin cues for guiding migrations in C. elegans. Neuron 16, 35–46 (1996).

    Article  CAS  Google Scholar 

  20. Mitchell, K. J. et al. Genetic analysis of Netrin genes in Drosophila: netrins guide CNS commissural axons and peripheral motor axons. Neuron 17, 203–215 (1996).

    Article  CAS  Google Scholar 

  21. Harris, R., Sabatelli, L. M. & Seeger, M. A. Guidance cues at the drosophila CNS midline: identification and characterization of two Drosophila Netrin/UNC-6 homologs. Neuron 17, 217–228 (1996).

    Article  CAS  Google Scholar 

  22. Chan, S. S.-Y. et al. UNC-40, a C. elegans homolog of DCC (deleted in colorectal cancer), is required in motile cells responding to UNC-6 netrin cues. Cell 87, 187–195 (1996).

    Article  CAS  Google Scholar 

  23. Kolodziej, P. A. et al. frazzled encodes a Drosophila member of the DCC immunoglobulin subfamily and is required for CNS and motor axon guidance. Cell 87, 197–204 (1996).

    Article  CAS  Google Scholar 

  24. Gossler, A., Doetschman, T., Korn, R., Serfling, E. & Kemler, R. Transgenesis by means of blastocyst-derived embryonic stem cell lines. Proc. Natl Acad. Sci. USA 83, 9065–9069 (1986).

    Article  ADS  CAS  Google Scholar 

  25. Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).

    Article  CAS  Google Scholar 

  26. Fearon, E. in The Molecular Basis of Cancer (ed. Mendelsohn, J.) 340–355 (Saunders, Philadelphia, 1995).

    Google Scholar 

  27. Moser, A. R., Pitot, H. C. & Dove, W. F. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247, 322–324 (1990).

    Article  ADS  CAS  Google Scholar 

  28. Su, L. K. et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256, 668–670 (1992).

    Article  ADS  CAS  Google Scholar 

  29. Moser, A. R., Dove, W. F., Roth, K. A. & Gordon, J. I. The Min (multiple intestinal neoplasia) mutation: its effect on gut epithelial cell differentiation and interaction with a modifier system. J. Cell Biol. 116, 1517–1526 (1992).

    Article  CAS  Google Scholar 

  30. Justice, M. J. et al. A molecular genetic linkage map of mouse chromosome 18 reveals extensive linkage conservation with human chromosomes 5 and 18. Genomics 13, 1281–1288 (1992).

    Article  CAS  Google Scholar 

  31. Luongo, C. et al. Mapping of multiple intestinal neoplasia (Min) to proximal chromosome 18 of the mouse. Genomics 15, 3–8 (1993).

    Article  CAS  Google Scholar 

  32. Luongo, C., Moser, A. R., Gledhill, S. & Dove, W. F. Loss of Apc+ in intestinal adenomas from Min mice. Cancer Res. 54, 5947–5952 (1994).

    CAS  PubMed  Google Scholar 

  33. Levy, D. B. et al. Inactivation of both APC alleles in human and mouse tumors. Cancer Res. 54, 5953–5458 (1994).

    CAS  PubMed  Google Scholar 

  34. Laird, P. W. et al. Suppression of intestinal neoplasia by DNA hypomethylation. Cell 81, 197–205 (1995).

    Article  CAS  Google Scholar 

  35. Chandrasekaran, C. & Grodon, J. I. Cell lineage-specific and differentiation-dependent patterns of CCAAT/enhancer binding protein alpha expression in the gut epithelium of normal and transgenic mice. Proc. Natl Acad. Sci. USA 90, 8871–8875 (1993).

    Article  ADS  CAS  Google Scholar 

  36. Falk, P., Roth, K. A. & Gordon, J. I. Lectins are sensitive tools for defining the differentiation programs of mouse gut epithelial cell lineages. Am. J. Physiol. 266, G987–1003 (1994).

    CAS  PubMed  Google Scholar 

  37. Roth, K. A. & Gordon, J. I. Spatial differentiation of the intestinal epithelium: analysis of enteroendocrine cells containing immunoreactive serotonin, secretin, and substance P in normal and transgenic mice. Proc. Natl Acad. Sci. USA 87, 6408–6412 (1990).

    Article  ADS  CAS  Google Scholar 

  38. Hedrick, L. et al. The DCC gene product in cellular differentiation and colorectal tumorigenesis. Genes Dev. 8, 1174–1183 (1994).

    Article  CAS  Google Scholar 

  39. Bry, L. et al. Paneth cell differentiation in the developing intestine of normal and transgenic mice. Proc. Natl Acad. Sci. USA 91, 10335–10339 (1994).

    Article  ADS  CAS  Google Scholar 

  40. Louvard, D., Kedinger, M. & Hauri, H. P. The differentiating intestinal epithelial cell: establishment and maintenance of functions through interactions between cellular structures. Annu. Rev. Cell Biol. 8, 157–195 (1992).

    Article  CAS  Google Scholar 

  41. Schmidt, G. H., Winton, D. J. & Ponder, B. A. Development of the pattern of cell renewal in the crypt-villus unit of chimaeric mouse small intestine. Development 103, 785–790 (1988).

    CAS  PubMed  Google Scholar 

  42. Hermiston, M. L., Green, R. P. & Gordon, J. I. Chimeric-transgenic mice represent a powerful tool for studying how the proliferation and differentiation programs of intestinal epithelial cell lineages are regulated. Proc. Natl Acad. Sci. USA 90, 8866–8870 (1993).

    Article  ADS  CAS  Google Scholar 

  43. Hermiston, M. L. & Gordon, J. I. In vivo analysis of cadherin function in the mouse intestinal epithelium: essential roles in adhesion, maintenance of differentiation, and regulation of programmed cell death. J. Cell Biol. 129, 489–506 (1995).

    Article  CAS  Google Scholar 

  44. Dodd, J., Morton, S. B., Karagogeos, D., Yamamoto, M. & Jessell, T. M. Spatial regulation of axonal glycoprotein expression on subsets of embryonic spinal neurons. Neuron 1, 105–116 (1988).

    Article  CAS  Google Scholar 

  45. Hohne, M. W., Halatsch, M. E., Kahl, G. F. & Weinel, R. J. Frequent loss of expression of the potential tumor suppressor gene DCC in ductal pancreatic adenocarcinoma. Cancer Res. 52, 2616–2619 (1992).

    CAS  PubMed  Google Scholar 

  46. Hahn, S. A. et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271, 350–353 (1996).

    Article  ADS  CAS  Google Scholar 

  47. Goodman, C. S. The likeness of being: phylogenetically conserved molecular mechanisms of growth cone guidance. Cell 78, 353–356 (1994).

    Article  CAS  Google Scholar 

  48. Mortensen, R. M., Conner, D. A., Chao, S., Geisterfer-Lowrance, A. A. & Seidman, J. G. Production of homozygous mutant ES cells with a single targeting construct. Mol. Cell. Biol. 12, 2391–2395 (1992).

    Article  CAS  Google Scholar 

  49. Stoeckli, E. T. & Landmesser, L. T. Axonin-1, Nr-CAM, and Ng-CAM play different roles in the in vivo guidance of chick commissural neurons. Neuron 14, 1165–1179 (1995).

    Article  CAS  Google Scholar 

  50. Ekstrand, B. C., Mansfield, T. A., Bigner, S. H. & Fearon, E. R. Dcc expression is altered by multiple mechanisms in brain tumors. Oncogene 11, 2393–2402 (1995).

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02142, USA

    Amin Fazeli, Stephanie L. Dickinson, Robert V. Tighe, Clayton G. Small & Robert A. Weinberg

  2. Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, Missouri, 63110, USA

    Michelle L. Hermiston & Jeffrey I. Gordon

  3. Massachusetts Institute of Technology/Whitehead Institute Genome Center, Cambridge, Massachusetts, 02142, USA

    Robert G. Steen

  4. Howard Hughes Medical Institute and Department of Anatomy, Programs in Cell Biology, Developmental Biology and Neuroscience, University of California, San Francisco, California, 94143, USA

    Esther T. Stoeckli, Kazuko Keino-Masu, Masayuki Masu & Marc Tessier-Lavigne

  5. Department of Physiology, National Defense Medical College, Saitama, 359, Japan

    Kazuko Keino-Masu

  6. Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA

    Helen Rayburn

  7. Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland, 21207, USA

    Jonathan Simons

  8. Department of Pathology, Tufts University Schools of Medicine and Veterinary Medicine, Boston, Massachusetts, 02111, USA

    Roderick T. Bronson

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Fazeli, A., Dickinson, S., Hermiston, M. et al. Phenotype of mice lacking functional Deleted in colorectal cancer (Dec) gene. Nature 386, 796–804 (1997). https://doi.org/10.1038/386796a0

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