title: Heads, Shoulders, Elbows, Knees, and Toes: Modular Gdf5 Enhancers Control Different Joints in the Vertebrate Skeleton.
abstract: Synovial joints are crucial for support and locomotion in vertebrates, and are the frequent site of serious skeletal defects and degenerative diseases in humans. Growth and differentiation factor 5 (Gdf5) is one of the earliest markers of joint formation, is required for normal joint development in both mice and humans, and has been genetically linked to risk of common osteoarthritis in Eurasian populations. Here, we systematically survey the mouse Gdf5 gene for regulatory elements controlling expression in synovial joints. We identify separate regions of the locus that control expression in axial tissues, in proximal versus distal joints in the limbs, and in remarkably specific sub-sets of composite joints like the elbow. Predicted transcription factor binding sites within Gdf5 regulatory enhancers are required for expression in particular joints. The multiple enhancers that control Gdf5 expression in different joints are distributed over a hundred kilobases of DNA, including regions both upstream and downstream of Gdf5 coding exons. Functional rescue tests in mice confirm that the large flanking regions are required to restore normal joint formation and patterning. Orthologs of these enhancers are located throughout the large genomic region previously associated with common osteoarthritis risk in humans. The large array of modular enhancers for Gdf5 provide a new foundation for studying the spatial specificity of joint patterning in vertebrates, as well as new candidates for regulatory regions that may also influence osteoarthritis risk in human populations.
authors.affiliation: Department of Developmental Biology, Beckman Center B300, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Developmental Biology, Beckman Center B300, Stanford University School of Medicine, Stanford, California, United States of America.|Human Evolutionary Biology, Peabody Museum, Harvard University, Cambridge, Massachusetts, United States of America.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Terence D
authors.initials: TD
authors.lastname: Capellini
authors.affiliation: Miltenyi Biotec GmbH, Bergisch Gladbach, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schoor
authors.affiliation: Molecular Physiology and Biophysics and Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Doug P
authors.initials: DP
authors.lastname: Mortlock
authors.affiliation: Center for Tissue Regeneration and Repair, University of California Davis Medical Center, Sacramento, California, United States of America.
authors.forename: A Hari
authors.initials: AH
authors.lastname: Reddi
authors.affiliation: Department of Developmental Biology, Beckman Center B300, Stanford University School of Medicine, Stanford, California, United States of America.|Howard Hughes Medical Institute, Stanford University, Stanford, California, United States of America.
authors.forename: David M
authors.initials: DM
authors.lastname: Kingsley
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D005091:Exons / Q000235:genetics; D005121:Extremities / Q000254:growth & development / Q000473:pathology; D055428:Growth Differentiation Factor 5 / Q000235:genetics* / Q000378:metabolism; D006257:Head / Q000254:growth & development / Q000473:pathology; D006801:Humans; D007596:Joints / Q000254:growth & development / Q000473:pathology; D007717:Knee / Q000254:growth & development / Q000473:pathology; D051379:Mice; D010003:Osteoarthritis / Q000235:genetics* / Q000473:pathology; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D012782:Shoulder / Q000254:growth & development / Q000473:pathology; D012863:Skeleton / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D013582:Synovial Fluid / Q000378:metabolism; D014034:Toes / Q000254:growth & development / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014714:Vertebrates / Q000235:genetics* / Q000254:growth & development
chemical_list: C525893:GDF5 protein, human; C525894:Gdf5 protein, mouse; D055428:Growth Differentiation Factor 5; D014157:Transcription Factors