Animal models of fibrodysplasia ossificans progressiva

LaBonty, Melissa; Yelick, Pamela C.

doi:10.1002/dvdy.24606

Cited by 16 publications

(40 citation statements)

References 106 publications

(239 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The zebrafish model also offers numerous advantages to study FOP (reviewed in [14]). Their small size, rapid and transparent embryonic development, and high fecundity make them ideal for numerous large-scale screening methods, including in vivo drug and genetic modifier screening.…”

Section: Introductionmentioning

confidence: 99%

An Adult Zebrafish Model of Fibrodysplasia Ossificans Progressiva

LaBonty

Yelick

2018

Methods in Molecular Biology

Self Cite

View full text Add to dashboard Cite

Fibrodysplasia ossificans progressiva (FOP) is a rare human skeletal disease caused by constitutively activating mutations in the gene ACVR1, which encodes a type I BMP/TGFβ family member receptor. FOP is characterized by progressive heterotopic ossification (HO) of fibrous tissues, including skeletal muscle, tendons, and ligaments, as well as malformation of the big toes, vertebral fusions, and osteochondromas. Surgical interventions in patients often result in enhanced HO, which can exacerbate rather than improve diagnostic outcomes. As a result of these difficulties, a variety of animal models are needed to study human FOP. Here we describe the methods for creating and characterizing zebrafish conditionally expressing Acvr1lQ204D, the first adult zebrafish model for FOP.

show abstract

Section: Introductionmentioning

confidence: 99%

An Adult Zebrafish Model of Fibrodysplasia Ossificans Progressiva

LaBonty

Yelick

2018

Methods in Molecular Biology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Among these commonly used animals, the mouse ACVR1 is 98.4% identical to its human orthologue, whereas the zebrafish ACVR1 (Acvr1l) shows only 69% identity. However, the GS and kinase domains of the zebrafish receptor are more similar (85% identity) ( Yelick et al, 1998 ; LaBonty and Yelick, 2018 ), validating the use of both these model organisms for studying FOP. Because normal ACVR1 activity is required for gastrulation, neural crest differentiation and germ cell development in mouse, and for dorsal-ventral patterning in zebrafish, embryonic expression of the FOP-associated mutation results in lethality ( Chakkalakal et al, 2012 ; LaBonty et al, 2017 ).…”

Section: Animal Models In Fop Researchmentioning

confidence: 87%

“…Functional orthologues of human ACVR1 are found throughout the animal kingdom, and expression of the classical or atypical FOP mutant forms of the receptor has been shown to cause dysregulated BMP signalling in several laboratory animals, including Drosophila , mouse, chick and zebrafish ( Twombly et al, 2009 ; Chakkalakal et al, 2012 ; Haupt et al, 2014 ; LaBonty and Yelick, 2018 ) ( Table 2 ). Among these commonly used animals, the mouse ACVR1 is 98.4% identical to its human orthologue, whereas the zebrafish ACVR1 (Acvr1l) shows only 69% identity.…”

Section: Animal Models In Fop Researchmentioning

confidence: 99%

“…Because normal ACVR1 activity is required for gastrulation, neural crest differentiation and germ cell development in mouse, and for dorsal-ventral patterning in zebrafish, embryonic expression of the FOP-associated mutation results in lethality ( Chakkalakal et al, 2012 ; LaBonty et al, 2017 ). To circumvent this problem, conditionally expressed mutant forms of ACVR1 have been developed to model FOP in both mouse and zebrafish ( Table 2 ) ( Yu et al, 2008 ; Chakkalakal et al, 2012 ; Hatsell et al, 2015 ; LaBonty et al, 2017 ; LaBonty and Yelick, 2018 ).…”

Section: Animal Models In Fop Researchmentioning

confidence: 99%

See 1 more Smart Citation

Fibrodysplasia ossificans progressiva: current concepts from bench to bedside

Kaliya-Perumal

Carney

Ingham

2020

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

Heterotopic ossification (HO) is a disorder characterised by the formation of ectopic bone in soft tissue. Acquired HO typically occurs in response to trauma and is relatively common, yet its aetiology remains poorly understood. Genetic forms, by contrast, are very rare, but provide insights into the mechanisms of HO pathobiology. Fibrodysplasia ossificans progressiva (FOP) is the most debilitating form of HO. All patients reported to date carry heterozygous gain-of-function mutations in the gene encoding activin A receptor type I (ACVR1). These mutations cause dysregulated bone morphogenetic protein (BMP) signalling, leading to HO at extraskeletal sites including, but not limited to, muscles, ligaments, tendons and fascia. Ever since the identification of the causative gene, developing a cure for FOP has been a focus of investigation, and studies have decoded the pathophysiology at the molecular and cellular levels, and explored novel management strategies. Based on the established role of BMP signalling throughout HO in FOP, therapeutic modalities that target multiple levels of the signalling cascade have been designed, and some drugs have entered clinical trials, holding out hope of a cure. A potential role of other signalling pathways that could influence the dysregulated BMP signalling and present alternative therapeutic targets remains a matter of debate. Here, we review the recent FOP literature, including pathophysiology, clinical aspects, animal models and current management strategies. We also consider how this research can inform our understanding of other types of HO and highlight some of the remaining knowledge gaps.

show abstract

“…In addition, more common diseases such as myeloid leukemia ( Lefort and Maguer-Satta, 2020 ), chronic kidney disease ( Kajimoto et al, 2015 ), vascular calcification ( Derwall et al, 2012 ) and atherosclerosis ( Saeed et al, 2012 ) are also linked to overactive BMP signaling. Zebrafish have been used to study the causal involvement of BMP signaling in a variety of skeletal and ocular diseases ( Ye et al, 2009 ), including congenital FOP ( LaBonty and Yelick, 2018 ; Mucha et al, 2018 ), radioulnar synostosis ( Suzuki et al, 2020 ) and superior coloboma ( Hocking et al, 2018 ). Targeting overactive BMP signaling for therapeutic gain has promise, but will require selective intervention.…”

Section: Introductionmentioning

confidence: 99%

Cercosporamide inhibits bone morphogenetic protein receptor type I kinase activity in zebrafish

Hoeksma

Zon

Dijke

et al. 2020

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

Zebrafish models are well established tools for investigating underlying mechanisms of diseases. Here, we identified cercosporamide, a metabolite from the fungus Ascochyta aquiliqiae, as a potent bone morphogenetic protein receptor (BMPR) type I kinase inhibitor through a zebrafish embryo phenotypic screen. The developmental defects in zebrafish, including lack of the ventral fin induced by cercosporamide was strikingly similar as the phenotypes caused by renowned small molecule BMPR type I kinase inhibitors and inactivating mutations in zebrafish BMPRs. In mammalian cell-based assays, cercosporamide blocked BMP/SMAD-dependent transcriptional reporter activity and BMP-induced SMAD1/5-phosphorylation. Biochemical assays with a panel of purified recombinant kinases demonstrated that cercosporamide directly inhibited kinase activity of BMPRs type I (also called activin receptor-like kinases (ALKs)). In mammalian cells, cercosporamide selectively inhibited constitutively active BMPR type I-induced SMAD1/5 phosphorylation. Importantly, cercosporamide rescued the developmental defects caused by constitutively active Alk2 in zebrafish embryos. Taken together, we believe cercosporamide may be the first of a new class of molecules with potential to be developed further for clinical use against diseases that are causally linked to overactivation of BMPR signaling, including Fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma.

show abstract

Animal models of fibrodysplasia ossificans progressiva

Cited by 16 publications

References 106 publications

An Adult Zebrafish Model of Fibrodysplasia Ossificans Progressiva

An Adult Zebrafish Model of Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva: current concepts from bench to bedside

Cercosporamide inhibits bone morphogenetic protein receptor type I kinase activity in zebrafish

Contact Info

Product

Resources

About