Anterior visceral endoderm directs ventral morphogenesis and placement of head and heart via BMP2 expression.

In amniotes, ventral folding morphogenesis achieves gut internalization, linear heart tube formation, ventral body wall closure, and encasement of the fetus in extraembryonic membranes. Impairment of ventral morphogenesis results in human birth defects involving body wall, gut, and heart malformations and in mouse misplacement of head and heart. Absence of knowledge about genetic pathways and cell populations directing ventral folding in mammals has precluded systematic study of cellular mechanisms driving this vital morphogenetic process. We report tissue-specific mouse mutant analyses identifying the bone morphogenetic protein (BMP) pathway as a key regulator of ventral morphogenesis. BMP2 expressed in anterior visceral endoderm (AVE) signals to epiblast derivatives during gastrulation to orchestrate initial stages of ventral morphogenesis, including foregut development and positioning of head and heart. These findings identify unanticipated functions for the AVE in organizing the gastrulating embryo and indicate that visceral endoderm-expressed BMP2 coordinates morphogenetic cell behaviors in multiple epiblast lineages.