Evidence for Involvement of Activin A and Bone Morphogenetic Protein 4 in Mammalian Mesoderm and Hematopoietic Development

TLDR

TGF‑β and FGF signaling have been shown to induce mesoderm in Xenopus, but functional evidence for these pathways during mouse mesoderm formation is lacking. Mouse embryonic stem cells can be directed to mesodermal fates in a serum‑free chemically defined medium. In this medium, activin A promotes dorsoanterior‑like mesoderm while BMP4 drives ventral mesoderm and hematopoietic precursors, and these effects are absent with other TGF‑β or FGF ligands, supporting a key role for TGF‑β family signaling in mammalian mesoderm and blood development.

Abstract

AbstractXenopus in vitro studies have implicated both transforming growth factor β (TGF-β) and fibroblast growth factor (FGF) families in mesoderm induction. Although members of both families are present during mouse 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 vitro in a chemically defined medium (CDM) in the absence of fetal bovine serum. In CDM, this differentiation is responsive to TGF-β family members in a concentration-dependent manner, with activin A mediating the formation of dorsoanterior-like mesoderm and bone morphogenetic protein 4 mediating the formation of ventral mesoderm, including hematopoietic precursors. These effects are not observed in CDM alone or when TGF-β1, -β2, or -β3, acid FGF, or basic FGF is added individually to CDM. In vivo, at day 6.5 of mouse development, activin βA RNA is detectable in the decidua and bone morphogenetic protein 4 RNA is detectable in the egg cylinder. Together, our data strongly implicate the TGF-β family in mammalian mesoderm development and hematopoietic cell formation.