The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo

  1. Christian Sirard1,2,6,
  2. José Luis de la Pompa1,2,6,
  3. Andrew Elia1,2,
  4. Annick Itie1,2,
  5. Christine Mirtsos1,2,
  6. Alison Cheung1,2,
  7. Stephan Hahn3,
  8. Andrew Wakeham1,2,
  9. Lois Schwartz4,5,
  10. Scott E. Kern3,
  11. Janet Rossant4,5, and
  12. Tak W. Mak1,2,7
  1. 1Amgen Institute, Toronto, Ontario M5G 2C1, Canada; 2Ontario Cancer Institute and Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario M5G 2C1, Canada; 3Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 USA; 4Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada; 5Departments of Molecular and Medical Genetics, and Obstetrics and Gynecology, University of Toronto, Toronto, Ontario M5G 2C1, Canada

Abstract

Mutations in the SMAD4/DPC4 tumor suppressor gene, a key signal transducer in most TGFβ-related pathways, are involved in 50% of pancreatic cancers. Homozygous Smad4 mutant mice die before day 7.5 of embryogenesis. Mutant embryos have reduced size, fail to gastrulate or express a mesodermal marker, and show abnormal visceral endoderm development. Growth retardation of theSmad4-deficient embryos results from reduced cell proliferation rather than increased apoptosis. Aggregation of mutant Smad4 ES cells with wild-type tetraploid morulae rescues the gastrulation defect. These results indicate that Smad4 is initially required for the differentiation of the visceral endoderm and that the gastrulation defect in the epiblast is secondary and non-cell autonomous. Rescued embryos show severe anterior truncations, indicating a second important role for Smad4 in anterior patterning during embryogenesis.

Keywords

Footnotes

  • 6 These authors contributed equally to this work.

  • 7 Corresponding author.

  • E-MAIL tmak{at}oci.utoronto.ca; FAX (416) 204-5300.

    • Received September 29, 1997.
    • Accepted October 24, 1997.
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