Division of Craniofacial and Molecular Genetics, Tufts University School of Dental Medicine, Boston, Massachusetts, USA.
Department of Biology, Faculty of Science, University of Ottawa, Ottawa, Ontario, Canada.
Dev Dyn. 2023 May;252(5):605-628. doi: 10.1002/dvdy.566. Epub 2023 Jan 26.
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, ACVR1 , shows increased bone morphogenetic protein (BMP) signaling and activation by activins.
Here, we performed in vivo functional characterization of human ACVR1 and orthologous zebrafish Acvr1l using early embryonic zebrafish dorsoventral patterning as a phenotypic readout for receptor activity. Our results showed that human ACVR1 and zebrafish Acvr1l exhibit functional differences in early embryonic zebrafish, and that human ACVR1 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 ACVR1 signaling in early embryonic zebrafish.
Together, these data provide new insight into ACVR1 signaling pathways that may facilitate the design of new and effective therapies for FOP patients.
纤维性骨发育不良进行性骨化（FOP）是一种罕见的疾病，其特征是肌肉和结缔组织的进行性异位骨化，由 I 型受体 ACVR1/ALK2 的常染色体显性激活突变引起。经典的人类 FOP 变体 ACVR1 表现出增加的骨形态发生蛋白（BMP）信号传导，并被激活素激活。
在这里，我们使用早期胚胎斑马鱼背腹模式形成作为受体活性的表型读出，对人类 ACVR1 和同源斑马鱼 Acvr1l 进行了体内功能特征分析。我们的结果表明，人类 ACVR1 和斑马鱼 Acvr1l 在早期胚胎斑马鱼中表现出功能差异，并且人类 ACVR1 在没有配体结合域（LBD）的情况下保留其信号转导活性。我们还首次表明，斑马鱼 Acvr2ba/Acvr2bb 受体对于人类 ACVR1 在早期胚胎斑马鱼中的信号转导是必需的。
这些数据为 ACVR1 信号通路提供了新的见解，可能有助于为 FOP 患者设计新的有效治疗方法。
