BMP4 initiates and patterns ventral-caudal structures in zebrafish and human pluripotent stem cell aggregates.

The formation of body axes is a key developmental milestone in vertebrate embryos and is guided by specialized groups of cells known as organizers. The molecular nature of organizers has been extensively investigated across the vertebrate kingdom; however, the minimal conditions and factors sufficient to guide embryogenesis and organogenesis-particularly in humans-remain incompletely understood. Here, we show that BMP4 alone, when administered at an appropriate dosage, is sufficient to induce the formation of an organizer for ventral-caudal-like structure (VCLS) formation. This organizer directs endoderm-deficient ventral-caudal cell fate specification and morphogenesis in zebrafish embryos. In 3D human pluripotent stem cell (hPSC) aggregates, BMP4 can induce an elongated embryonic structure that is characterized by ventral-caudal cell fates. Importantly, hPSCs instructed by BMP4 are sufficient to induce a secondary posterior axis when grafted into the animal pole of the zebrafish embryo. Our study thus uncovers BMP4 as the inducer for the formation of a ventral-caudal organizer in the vertebrate embryo.