Functional comparison of human ACVR1 and zebrafish Acvr1l FOP‐associated variants in embryonic zebrafish

Background Fibrodysplasia ossificans progressiva (FOP), a rare disease characterized by progressive heterotopic ossification of muscle and connective tissues, is caused by autosomal dominant activating mutations in the type I receptor, ACVR1/ALK2. The classic human FOP variant, ACVR1R206H, shows inc...

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Published in:	Developmental dynamics Vol. 252; no. 5; pp. 605 - 628
Main Authors:	Lalonde, Robert L., Nicolas, Hannah A., Cutler, Rowan S., Pantekidis, Irene, Zhang, Weibo, Yelick, Pamela C.
Format:	Journal Article
Language:	English
Published:	Hoboken, USA John Wiley & Sons, Inc 01-05-2023 Wiley Subscription Services, Inc
Subjects:	Activin Receptors, Type I - genetics Animals BMP signaling Bone morphogenetic proteins Connective tissue diseases Connective tissues Danio rerio dorsoventral patterning early embryonic zebrafish Embryo, Nonmammalian - metabolism Embryogenesis FOP Humans Mutation Myositis Ossificans Ossification (ectopic) Ossification, Heterotopic Pattern formation Receptors Signal Transduction Signaling transgenic heat‐shock inducible zebrafish Zebrafish BMP signaling dorsoventral patterning FOP early embryonic zebrafish transgenic heat-shock inducible zebrafish
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Summary:	Background Fibrodysplasia ossificans progressiva (FOP), a rare disease characterized by progressive heterotopic ossification of muscle and connective tissues, is caused by autosomal dominant activating mutations in the type I receptor, ACVR1/ALK2. The classic human FOP variant, ACVR1R206H, shows increased bone morphogenetic protein (BMP) signaling and activation by activins. Results Here, we performed in vivo functional characterization of human ACVR1R206H and orthologous zebrafish Acvr1lR203H using early embryonic zebrafish dorsoventral patterning as a phenotypic readout for receptor activity. Our results showed that human ACVR1R206H and zebrafish Acvr1lR203H exhibit functional differences in early embryonic zebrafish, and that human ACVR1R206H retained its signaling activity in the absence of a ligand‐binding domain (LBD). We also showed, for the first time, that zebrafish Acvr2ba/Acvr2bb receptors are required for human ACVR1R206H signaling in early embryonic zebrafish. Conclusions Together, these data provide new insight into ACVR1R206H signaling pathways that may facilitate the design of new and effective therapies for FOP patients. Key Findings Human ACVR1‐R206H mediates upregulated BMP signaling in embryonic zebrafish. The orthologous zebrafish Acvr1l‐R203H variant does not exhibit upregulated BMP signaling. Zebrafish Acvr2ba/Acvr2bb is required for human ACVR1‐R206H signaling in embryonic zebrafish.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 R. L. L. performed all experimentation except for western blots analysis and wrote the manuscript. R. L. L. and P. C. Y. conceptualized the project. R.S.C, W.Z. and P.C.Y. performed western blot analysis. I. P. propagated the transgenic and mutant lines. R. L. L., H.A.N and P. C. Y. analyzed the data. P. C. Y. supervised the project, secured funding, and revised the manuscript. Author Contributions
ISSN:	1058-8388 1097-0177
DOI:	10.1002/dvdy.566