LaBonty Melissa, Pray Nicholas, Yelick Pamela C
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.
Zebrafish. 2018 Dec;15(6):536-545. doi: 10.1089/zeb.2018.1611. Epub 2018 Sep 5.
Fibrodysplasia Ossificans Progressiva (FOP) is a rare, autosomal dominant genetic disorder in humans characterized by the gradual ossification of fibrous tissues, including skeletal muscle, tendons, and ligaments. In humans, mutations in the Type I BMP/TGFβ family member receptor gene, ACVR1, are associated with FOP. Zebrafish acvr1l, previously known as alk8, is the functional ortholog of human ACVR1. We previously created and characterized the first adult zebrafish model for FOP by generating animals harboring heat shock-inducible mCherry-tagged constitutively active Acvr1l (Q204D). Since injury is a known trigger for heterotopic ossification (HO) development in human FOP patients, in this study, we investigated several injury models in Acvr1l-expressing zebrafish and the subsequent formation of HO. We performed studies of Activin A injection, cardiotoxin (CTX) injection, and caudal fin clip injury. We found that none of these methods resulted in HO formation at the site of injury. However, some of the cardiotoxin-injected and caudal fin-clipped animals did exhibit HO at distant sites, including the body cavity and along the spine. We describe these results in the context of new and exciting reports on FOP, and discuss future studies to better understand the etiology and progression of this disease.
进行性骨化性纤维发育不良（FOP）是一种罕见的常染色体显性遗传病，其特征是纤维组织（包括骨骼肌、肌腱和韧带）逐渐骨化。在人类中，I型骨形态发生蛋白/转化生长因子β家族成员受体基因ACVR1的突变与FOP相关。斑马鱼acvr1l，以前称为alk8，是人类ACVR1的功能直系同源基因。我们之前通过生成携带热休克诱导的mCherry标记的组成型活性Acvr1l（Q204D）的动物，创建并表征了首个用于FOP的成年斑马鱼模型。由于损伤是人类FOP患者异位骨化（HO）发展的已知触发因素，在本研究中，我们研究了几种在表达Acvr1l的斑马鱼中的损伤模型以及随后HO的形成。我们进行了激活素A注射、心脏毒素（CTX）注射和尾鳍夹伤的研究。我们发现这些方法均未导致损伤部位形成HO。然而，一些注射了心脏毒素和尾鳍被夹伤的动物确实在远处部位出现了HO，包括体腔和沿脊柱部位。我们结合关于FOP的新的和令人兴奋的报告来描述这些结果，并讨论未来的研究以更好地理解这种疾病的病因和进展。
