Drosophila models of FOP provide mechanistic insight

Abstract Fibrodysplasia ossificans progressiva (FOP) is a rare bone disease characterized by episodic events of heterotopic ossification (HO). All cases of FOP have been attributed to mutations in the ACVR1 gene that render the encoded BMP type I ALK2 receptor hypersensitive, resulting in the activation of BMP signaling, at inappropriate times in inappropriate locations. The episodic or sporadic nature of HO associated with FOP rests with the occurrence of specific ‘triggers’ that push the hypersensitive ALK2-FOP receptor into full signaling mode. Identification of these triggers and their mechanism of action is critical for preventing HO and its devastating consequences in FOP patients. Models of FOP, generated in Drosophila , are shown to activate the highly conserved BMP signaling pathway in both Drosophila cell culture and in developing tissues in vivo . The most common FOP mutation, R206H, in ALK2 and its synonymous mutation, K262H, in the orthologous Drosophila receptor Sax, abolish the ability of wild type receptors to inhibit BMP ligand-induced signaling and lead to ubiquitous pathway activation in both cases but with important differences. When expressed in Drosophila , human ALK2 R206H exhibits constitutive signaling. Sax K262H on the other hand can elicit excessive signaling similar to that observed for ALK2 R206H in mammalian systems in vivo . For example, hyperactive signaling mediated by Sax K262H is triggered by an increase in ligand or in type II receptors. Interestingly, while the constitutive nature of ALK2 R2026H in Drosophila requires activation by the type II receptor, it does not require its ligand binding domain. The differences exhibited by the two Drosophila FOP models enable a valuable comparative analysis poised to reveal critical regulatory mechanisms governing signaling output from these mutated receptors. Modifier screens using these Drosophila FOP models will be extremely valuable in identifying genes or compounds that reduce or prevent the hyperactive BMP signaling that initiates HO associated with FOP.