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

Christian Sirard, José Luis De La Pompa, Andrew Elia, Annick Itie, Christine Mirtsos, Alison Cheung, Stephan Hahn, Andrew Wakeham, Lois Schwartz, Scott E. Kern, Janet Rossant, Tak W. Mak

Research output: Contribution to journalArticle

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 the Smad4-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.

Original languageEnglish (US)
Pages (from-to)107-119
Number of pages13
JournalGenes and Development
Volume12
Issue number1
DOIs
StatePublished - Jan 1 1998

Keywords

  • Anterior development
  • Gastrulation
  • Smad4/Dpc4 mutant mice
  • Visceral endoderm

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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  • Cite this

    Sirard, C., De La Pompa, J. L., Elia, A., Itie, A., Mirtsos, C., Cheung, A., Hahn, S., Wakeham, A., Schwartz, L., Kern, S. E., Rossant, J., & Mak, T. W. (1998). The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo. Genes and Development, 12(1), 107-119. https://doi.org/10.1101/gad.12.1.107