The type I serine threonine kinase receptor ActRIA (ALK2) is required for gastrulation of the mouse embryo

ActRIA (or ALK2), one of the type I receptors of the transforming growth fa ctor-beta (TGF-beta) superfamily, can bind both activin and bone morphogene tic proteins (BMPs) in conjunction with the activin and BMP type II recepto rs, respectively. In mice, ActRIA is expressed primarily in the extraembryo nic visceral endoderm before gastrulation and later in both embryonic and e xtraembryonic cells during gastrulation. To elucidate its function in mouse development, we disrupted the transmembrane domain of ActRIA by gene targe ting. We showed that embryos homozygous for the mutation were arrested at t he early gastrulation stage, displaying abnormal visceral endoderm morpholo gy and severe disruption of mesoderm formation. To determine in which germ layer ActRIA functions during gastrulation, we performed reciprocal chimera analyses. (1) Homozygous mutant ES cells injected into wild-type blastocys ts were able to contribute to all three definitive germ layers in chimeric embryos. However, a high contribution of mutant ES cells in chimeras disrup ted normal development at the early somite stage. (2) Consistent with ActRI A expression in the extraembryonic cells, wild-type ES cells failed to resc ue the gastrulation defect in chimeras in which the extraembryonic ectoderm and visceral endoderm were derived from homozygous mutant blastocysts, Fur thermore, expression of HNF4, a key visceral endoderm-specific transcriptio n regulatory factor, was significantly reduced in the mutant embryos. Toget her, our results indicate that ActRIA in extraembryonic cells plays a major role in early gastrulation, whereas ActRIA function is also required in em bryonic tissues during later development in mice.