BMP heterodimers assemble hetero-type I receptor complexes that pattern the DV axis

Patterning the embryonic dorsoventral (DV) axis of both vertebrates and invertebrates requires signaling via Bone Morphogenetic Proteins (BMPs)1. Although a well studied process, the physiologically relevant BMP signaling complex in the Drosophila embryo is controversial2, 3 and generally inferred from cell culture studies, and has not been investigated in vertebrates. Here, we demonstrate that DV patterning in zebrafish requires two classes of nonredundant type I BMP receptors, Alk3/6 and Alk8. We show under physiologic conditions in the embryo that these two type I receptor classes form a complex in a manner that depends on both Bmp2 and Bmp7. We found that both Bmp2/7 heterodimers, as well as Bmp2 and Bmp7 homodimers, form in the embryo. However, only recombinant ligand heterodimers can activate BMP signaling in the early embryo, whereas a combination of Bmp2 and Bmp7 homodimers cannot. We propose that only heterodimers, signaling via two distinct classes of type I receptor, possess sufficient receptor affinity in an environment of extracellular antagonists to elicit the signaling response required for DV patterning.