Morphogen receptor genes and metamorphogenes: skeleton keys to metamorphosis.
Morphogen receptors are nodal points in signal transduction pathways that regulate morphogenesis during embryonic development. A recent discovery identified a recurrent missense mutation in a gene encoding a morphogen receptor responsible for the elusive process of skeletal metamorphosis in humans. Metamorphosis, the postnatal transformation of one normal tissue or organ system into another, is a biological process rarely seen in higher vertebrates or mammals, but exemplified pathologically by the disabling autosomal dominant disorder, fibrodysplasia ossificans progressiva (FOP). Individuals with FOP experience episodes of spontaneous or trauma-induced metamorphosis that convert normal functioning aponeuroses, fascia, ligaments, tendons, and skeletal muscles into a highly ramified and disabling second skeleton of heterotopic bone. The recurrent single nucleotide missense mutation in the gene encoding activin receptor IA/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor that causes FOP in all classically affected individuals worldwide, is one of the most specific disease-causing mutations in the human genome and the first identified human metamorphogene. These findings provide deep insight into a signaling pathway that regulates tissue and organ stability following morphogenesis, and that when dysregulated in a specific manner, orchestrates the metamorphosis of one normal tissue or organ system into another. The study of skeletal metamorphosis in FOP provides profound insight into the molecular mechanisms that ensure phenotypic stability following morphogenesis and that ordinarily lay deeply hidden in the highly conserved signaling pathways that regulate cell fate. Such insight is applicable to a broad range of human afflictions.
Kaplan
Frederick S
FS
Department of Orthopaedic Surgery and Medicine, The University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. frederick.kaplan@uphs.upenn.edu
Groppe
Jay
J
Pignolo
Robert J
RJ
Shore
Eileen M
EM
D000818:Animals; D044127:Epigenesis, Genetic; D006801:Humans; D008675:Metamorphosis, Biological; D009024:Morphogenesis / Q000235:genetics*; D020125:Mutation, Missense; D011956:Receptors, Cell Surface / Q000235:genetics*; D023822:Tissue Engineering
D011956:Receptors, Cell Surface