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Fibrodysplasia ossificans progressiva mutant ACVR1 signals by multiple modalities in the developing zebrafish.
Elife. 2020 09 08; 9E

Abstract

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.

Authors+Show Affiliations

Department of Cell and Developmental Biology University of Pennsylvania Perelman School of Medicine, Philadelphia, United States. Departments of Orthopaedic Surgery and Genetics University of Pennsylvania Perelman School of Medicine, Philadelphia, United States.Department of Cell and Developmental Biology University of Pennsylvania Perelman School of Medicine, Philadelphia, United States.Departments of Orthopaedic Surgery and Genetics University of Pennsylvania Perelman School of Medicine, Philadelphia, United States.Department of Cell and Developmental Biology University of Pennsylvania Perelman School of Medicine, Philadelphia, United States.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32897189

Citation

Allen, Robyn S., et al. "Fibrodysplasia Ossificans Progressiva Mutant ACVR1 Signals By Multiple Modalities in the Developing Zebrafish." ELife, vol. 9, 2020.
Allen RS, Tajer B, Shore EM, et al. Fibrodysplasia ossificans progressiva mutant ACVR1 signals by multiple modalities in the developing zebrafish. Elife. 2020;9.
Allen, R. S., Tajer, B., Shore, E. M., & Mullins, M. C. (2020). Fibrodysplasia ossificans progressiva mutant ACVR1 signals by multiple modalities in the developing zebrafish. ELife, 9. https://doi.org/10.7554/eLife.53761
Allen RS, et al. Fibrodysplasia Ossificans Progressiva Mutant ACVR1 Signals By Multiple Modalities in the Developing Zebrafish. Elife. 2020 09 8;9 PubMed PMID: 32897189.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fibrodysplasia ossificans progressiva mutant ACVR1 signals by multiple modalities in the developing zebrafish. AU - Allen,Robyn S, AU - Tajer,Benjamin, AU - Shore,Eileen M, AU - Mullins,Mary C, Y1 - 2020/09/08/ PY - 2019/11/21/received PY - 2020/08/12/accepted PY - 2020/9/8/entrez PY - 2020/9/9/pubmed PY - 2021/2/12/medline KW - bmp signaling KW - developmental biology KW - dorsal-ventral patterning KW - fibrodysplasia ossificans progressiva KW - ligand-binding independent signaling KW - ligand-responsive signaling KW - zebrafish JF - eLife JO - Elife VL - 9 N2 - 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. SN - 2050-084X UR - https://www.unboundmedicine.com/medline/citation/32897189/Fibrodysplasia_ossificans_progressiva_mutant_ACVR1_signals_by_multiple_modalities_in_the_developing_zebrafish_ L2 - https://doi.org/10.7554/eLife.53761 DB - PRIME DP - Unbound Medicine ER -