RRC ID 21911
Author Le VQ, Wharton KA.
Title Hyperactive BMP signaling induced by ALK2(R206H) requires type II receptor function in a Drosophila model for classic fibrodysplasia ossificans progressiva.
Journal Dev Dyn
Abstract BACKGROUND:Fibrodysplasia Ossificans Progressiva (FOP) is an autosomal dominant disorder characterized by episodic deposition of heterotopic bone in place of soft connective tissue. All FOP-associated mutations map to the BMP type I receptor, ALK2, with the ALK2(R206H) mutant form found in the vast majority of patients. The mechanism(s) regulating the expressivity of hyperactive ALK2(R206H) signaling throughout a patient's life is not well understood.
RESULTS:In Drosophila, human ALK2(R206H) receptor induces hyperactive BMP signaling. As in vertebrates, elevated signaling associated with ALK2(R206H) in Drosophila is ligand-independent. We found that a key determinant for ALK2(R206H) hyperactivity is a functional type II receptor. Furthermore, our results indicate that like its Drosophila ortholog, Saxophone (Sax), wild-type ALK2 can antagonize, as well as promote, BMP signaling.
CONCLUSIONS:The dual function of ALK2 is of particular interest given the heterozygous nature of FOP, as the normal interplay between such disparate behaviors could be shifted by the presence of ALK2(R206H) receptors. Our studies provide a compelling example for Drosophila as a model organism to study the molecular underpinnings of complex human syndromes such as FOP.
Volume 241(1)
Pages 200-14
Published 2012-1-1
DOI 10.1002/dvdy.22779
PMID 22174087
PMC PMC3454517
MeSH Activin Receptors, Type I / genetics Activin Receptors, Type I / metabolism* Animals Bone Morphogenetic Protein Receptors, Type II / genetics Bone Morphogenetic Protein Receptors, Type II / metabolism* Bone Morphogenetic Proteins / genetics Bone Morphogenetic Proteins / metabolism* Disease Models, Animal Drosophila Proteins / genetics Drosophila Proteins / metabolism Drosophila melanogaster / anatomy & histology Drosophila melanogaster / physiology* Humans Myositis Ossificans / physiopathology* Receptors, Transforming Growth Factor beta / genetics Receptors, Transforming Growth Factor beta / metabolism Signal Transduction / physiology* Wings, Animal / anatomy & histology Wings, Animal / physiology
IF 2.852
Times Cited 26
Drosophila 7904R-2