title: A Zebrafish Model of Human Fibrodysplasia Ossificans Progressiva.
abstract: Fibrodysplasia ossificans progressiva (FOP) is a rare, autosomal dominant genetic disorder in humans characterized by explosive inflammatory response to injury leading to gradual ossification within fibrous tissues, including skeletal muscle, tendons, and ligaments. A variety of animal models are needed to study and understand the etiology of human FOP. To address this need, here we present characterizations of the first adult zebrafish model for FOP. In humans, activating mutations in the Type I BMP/TGFβ family member receptor, ACVR1, are associated with FOP. Zebrafish acvr1l, previously known as alk8, is the functional ortholog of human ACVR1, and has been studied extensively in the developing zebrafish embryo, where it plays a role in early dorsoventral patterning. Constitutively active and dominant negative mutations in zebrafish acvr1l cause early lethal defects. Therefore, to study roles for activating acvr1l mutations in adult zebrafish, we created transgenic animals expressing mCherry-tagged, heat-shock-inducible constitutively active Acvr1l, Acvr1lQ204D, to investigate phenotypes in juvenile and adult zebrafish. Our studies showed that adult zebrafish expressing heat-shock-induced Acvr1lQ204Ddevelop a number of human FOP-like phenotypes, including heterotopic ossification lesions, spinal lordosis, vertebral fusions, and malformed pelvic fins. Together, these results suggest that transgenic zebrafish expressing heat-shock-inducible Acvr1lQ204Dcan serve as a model for human FOP.
authors.affiliation: 1 Program in Cell, Molecular, and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine , Boston, Massachusetts.|2 Division of Craniofacial and Molecular Genetics, Department of Orthodontics, Tufts University School of Dental Medicine , Boston, Massachusetts.
authors.forename: Melissa
authors.initials: M
authors.lastname: LaBonty
authors.affiliation: 2 Division of Craniofacial and Molecular Genetics, Department of Orthodontics, Tufts University School of Dental Medicine , Boston, Massachusetts.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Pray
authors.affiliation: 1 Program in Cell, Molecular, and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine , Boston, Massachusetts.|2 Division of Craniofacial and Molecular Genetics, Department of Orthodontics, Tufts University School of Dental Medicine , Boston, Massachusetts.
authors.forename: Pamela C
authors.initials: PC
authors.lastname: Yelick
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D019521:Body Patterning; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D018869:Heat-Shock Response; D006801:Humans; D009221:Myositis Ossificans / Q000235:genetics*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: D029961:Zebrafish Proteins; D030201:Activin Receptors, Type I; C424203:acvr1l protein, zebrafish
keywords: FOP; adult zebrafish disease model; heterotopic ossification