ZFIN ID: ZDB-PUB-200909-8
Fibrodysplasia ossificans progressiva mutant ACVR1 signals by multiple modalities in the developing zebrafish
Allen, R.S., Tajer, B., Shore, E.M., Mullins, M.C.
Date: 2020
Source: eLIFE   9: (Journal)
Registered Authors: Mullins, Mary C.
Keywords: bmp signaling, developmental biology, dorsal-ventral patterning, fibrodysplasia ossificans progressiva, ligand-binding independent signaling, ligand-responsive signaling, zebrafish
MeSH Terms:
  • Activin Receptors, Type I/genetics*
  • Activin Receptors, Type I/metabolism
  • Animals
  • Disease Models, Animal
  • Embryo, Nonmammalian/metabolism
  • Fish Proteins/genetics*
  • Fish Proteins/metabolism
  • Myositis Ossificans/genetics*
  • Myositis Ossificans/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics*
  • Zebrafish/growth & development
  • Zebrafish/metabolism
PubMed: 32897189 Full text @ Elife
Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic disorder characterized by altered skeletal development and extraskeletal ossification. All cases of FOP are caused by activating mutations in the type I BMP/TGFβ cell surface receptor ACVR1, which over-activates signaling through phospho-Smad1/5 (pSmad1/5). To investigate the mechanism by which FOP-ACVR1 enhances pSmad1/5 activation, we used zebrafish embryonic dorsoventral (DV) patterning as an assay for BMP signaling. We determined that the FOP mutants ACVR1-R206H and -G328R do not require their ligand binding domain to over-activate BMP signaling in DV patterning. However, intact ACVR1-R206H has the ability to respond to both Bmp7 and Activin A ligands. Additionally, BMPR1, a type I BMP receptor normally required for BMP-mediated patterning of the embryo, is dispensable for both ligand-independent signaling pathway activation and ligand-responsive signaling hyperactivation by ACVR1-R206H. These results demonstrate that FOP-ACVR1 is not constrained by the same receptor/ligand partner requirements as WT-ACVR1.