EVIDENCE FOR INVOLVEMENT OF ACTIVIN-A AND BONE MORPHOGENETIC PROTEIN-4 IN MAMMALIAN MESODERM AND HEMATOPOIETIC DEVELOPMENT

Xenopus in vitro studies have implicated both transforming growth fact or beta (TGF-beta) and fibroblast growth factor (FGF) families in meso derm induction. Although members of both families are present during m ouse mesoderm formation, there is little evidence for their functional role in mesoderm induction. We show that mouse embryonic stem cells, which resemble primitive ectoderm, can differentiate to mesoderm in vi tro in a chemically defined medium (CDM) in the absence of fetal bovin e serum. In CDM, this differentiation is responsive to TGF-beta family members in a concentration dependent manner, with activin A mediating the formation of dorsoanterior-like mesoderm and bone morphogenetic p rotein 4 mediating the formation of ventral mesoderm, including hemato poietic precursors. These effects are not observed in CDM alone or whe n TGF-beta 1, -beta 2, or -beta 3, acid FGF, or basic FGF is added ind ividually to CDM. In vivo, at day 6.5 of mouse development, activin be ta A RNA is detectable in the decidua and bone morphogenetic protein 4 RNA is detectable in the egg cylinder. Together, our data strongly im plicate the TGF-beta family in mammalian mesoderm development and hema topoietic cell formation.