title: The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo.
abstract: Mutations in the SMAD4/DPC4 tumor suppressor gene, a key signal transducer in most TGFbeta-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.
authors.affiliation: Amgen Institute, Toronto, Ontario M5G 2C1, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Sirard
authors.forename: J L
authors.initials: JL
authors.lastname: de la Pompa
authors.forename: A
authors.initials: A
authors.lastname: Elia
authors.forename: A
authors.initials: A
authors.lastname: Itie
authors.forename: C
authors.initials: C
authors.lastname: Mirtsos
authors.forename: A
authors.initials: A
authors.lastname: Cheung
authors.forename: S
authors.initials: S
authors.lastname: Hahn
authors.forename: A
authors.initials: A
authors.lastname: Wakeham
authors.forename: L
authors.initials: L
authors.lastname: Schwartz
authors.forename: S E
authors.initials: SE
authors.lastname: Kern
authors.forename: J
authors.initials: J
authors.lastname: Rossant
authors.forename: T W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000483:Alleles; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015197:Carcinogenicity Tests; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D005314:Embryonic and Fetal Development / Q000235:genetics / Q000502:physiology*; D004707:Endoderm / Q000502:physiology; D005260:Female; D005326:Fetal Proteins; D005775:Gastrula / Q000502:physiology*; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D051557:Hepatocyte Nuclear Factor 4; D006579:Heterozygote; D006720:Homozygote; D008297:Male; D008648:Mesoderm / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000378:metabolism; D051901:Smad4 Protein; D013234:Stem Cells / Q000166:cytology; D020825:T-Box Domain Proteins; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D000098908:Brachyury Protein
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D005326:Fetal Proteins; D051557:Hepatocyte Nuclear Factor 4; D010750:Phosphoproteins; D051901:Smad4 Protein; D020825:T-Box Domain Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000098908:Brachyury Protein; C490810:Smad4 protein, mouse; C501970:Tcfl4 protein, mouse