THE TUMOR-SUPPRESSOR GENE SMAD4 DPC4 IS REQUIRED FOR GASTRULATION ANDLATER FOR ANTERIOR DEVELOPMENT OF THE MOUSE EMBRYO/

Mutations in the SMAD4/DPC4 tumor suppressor gene, a key signal transd ucer in most TGF beta-related pathways, are involved in 50% of pancrea tic cancers. Homozygous Smad4 mutant mice die before day 7.5 of embryo genesis. Mutant embryos have reduced size, fail to gastrulate or expre ss a mesodermal marker, and show abnormal visceral endoderm developmen t. Growth retardation of the Smad4-deficient embryos results from redu ced cell proliferation rather than increased apoptosis. Aggregation of mutant Smad4 ES cells with wild-type tetraploid morulae rescues the g astrulation defect. These results indicate that Smad4 is initially req uired for the differentiation of the visceral endoderm and that the ga strulation defect in the epiblast is secondary and non-cell autonomous . Rescued embryos show severe anterior truncations, indicating a secon d important role for Smad4 in anterior patterning during embryogenesis .