Acvr2b receptors transduce all BMP signaling in the zebrafish gastrula and restrict Fibrodysplasia Ossificans Progressiva ACVR1-R206H signaling in a dose-dependent manner

BMP signaling drives dorsoventral (DV) axial patterning in vertebrates and invertebrates, with BMP dimers recruiting tetrameric receptor complexes to phosphorylate SMADs that activate ventral target gene expression. In zebrafish DV patterning, BMP2/7 heterodimers exclusively signal, assembling a receptor complex of two distinct type I receptors, Bmpr1 and Acvr1l, that canonically bind Bmp2 and Bmp7 ligands, respectively. We tested if the two distinct classes of BMP type II receptors, Bmpr2 and Acvr2, also act in the signaling complex. We determined that Acvr2 receptors solely transduce BMP signaling in DV patterning. We mutated all four acvr2a and acvr2b genes in the zebrafish and found that maternal-zygotic depletion of just Acvr2b receptors abrogates all BMP signaling, indicating that Acvr2b is the primary type II receptor transducing BMP signaling in the gastrula. We further demonstrated that hyperactive signaling through the ACVR1-R206H Fibrodysplasia Ossificans Progressiva human disease-causing mutant receptor is restricted when maternal and zygotic contributions of either Acvr2ba or Acvr2bb are absent. This reveals an increased sensitivity of ACVR1-R206H signaling to Acvr2b dosage, compared to wild-type ACVR1. These findings support a model in which Acvr2b receptors mediate the endogenous BMP signaling in the gastrula and that hyperactivity of ACVR1-R206H is limited in a dose-dependent manner by the relative concentration of Acvr2b.