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 TGF␤-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.

Roles of TGF-β family signaling in stem cell renewal and differentiation

“…Mouse embryos deficient in Smad4 display defective epiblast proliferation and delayed outgrowth of the inner cell mass [13], and mice lacking ALK-3 bone morphogenetic protein (BMP) type IA receptor) exhibit reduced cell proliferation in the epiblast [14], demonstrating that BMP signaling plays important roles in the maintenance of mouse ES cell identity. Qi et al [15] reported that BMP-4 provided by feeder cells is necessary for the maintenance of ES cell self-renewal, and that effect of BMP-4 is accomplished by means of inhibition of both extracellular receptor kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) pathways.…”

Regulation of cell proliferation by Smad proteins

“…Smad4 knock-out mice die between E7.5 and E8.5, and show growth retardation, no mesoderm formation, no gastrulation, and abnormal visceral endoderm development. The gastrulation defect of Smad4 null mice was rescued when a mutant embryos were surrounded by wild-type extraembryonic tissue (Sirard et al, 1998;Yang et al, 1998). Heterozygous Smad4 mice survive and develop malignant intestinal tumors after 1 year of age (Takaku et al, 1999;, most likely due to a loss of heterozygosity and reduplication of the mutated Smad4 allele (Takaku et al, 1999).…”

Mouse models for colorectal cancer

“…In mice, inactivation of the Smad4 gene leads to embryonic lethality. Heterozygous mice do not display a cancer phenotype up to 1 year of age (Sirard et al, 1998). If a Smad4 mutation is combined with an Apc mutation, it was shown that the progression was enhanced and the endpoint of tumorigenesis was more malignant (Takaku et al, 1998).…”