Multiple roles for activin-like kinase-2 signaling during mouse embryogenesis

The members of the transforming growth factor-β (TGF-β) superfamily are secreted proteins that interact with cell-surface receptors to elicit signals that regulate a variety of biological processes during vertebrate embryogenesis. A1k2, also known as ActRIA, Tsk7L, and SKR1, encodes a type I TGF-β family receptor for activins and BMP-7. Initially, A1k2 transcripts are detected in the visceral endoderm of gastrula stage mouse embryos, suggesting a signaling role in extraembryonic tissues during development. To study the role of A1k2 during mammalian development, A1k2 mutant mice were generated. After embryonic day 9.5 (E9.5), no homozygous mutants were recovered from heterozygote matings. Homozygous mutants with morphological defects were first detected at E7.0 and were smaller than controls. Morphological and molecular examination demonstrated that A1k2 mutant embryos formed a primitive streak, although abnormally thickened, and were arrested in their development around the late streak stage. These gastrulation defects were rescued in chimeric embryos generated by injection of A1k2 mutant embryonic stem (ES) cells into wild-type blastocysts. This rescue of gastrulation defects was also observed in chimeric embryos generated by aggregation of A1k2 homozygous mutant ES cells with tetraploid wild-type embryos. However, at E9.5, these embryos that were completely ES-derived also had defects. In contrast, chimeric embryos generated by injection of wild- type ES cells into A1k2 mutant blastocysts did not show rescue of the gastrulation defects. These results suggest that signaling through this type I receptor is essential in extraembryonic tissues at the time of gastrulation for normal mesoderm formation and also suggest that subsequent A1k2 signaling is essential for normal development after gastrulation.