ArticlePLoS genetics2016
Heads, Shoulders, Elbows, Knees, and Toes: Modular Gdf5 Enhancers Control Different Joints in the Vertebrate Skeleton.
Article in PLoS genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 2 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
52 citing papers in PubMed, 2 syntheses or guidelines pooled it, 77 citations in OpenAlex.
- Genetics of hip dysplasia - a systematic literature review.BMC musculoskeletal disorders · 2024Pooled it
- Pooled it
- Epigenetic regulation of vertebrate limb development: from field specification to tissue morphogenesis.Epigenetics · 2026Review
- Signaling and transcriptional networks governing late synovial joint development.Developmental biology · 2026Article
- The roles of TGF-β, Wnt, and MAPK signaling pathways in joint lineage specification in vitro and ex vivo.Stem cell reports · 2025Article
- Complex Regulatory Interactions at GDF5 Shape Joint Morphology and Osteoarthritis Disease Risk.Arthritis & rheumatology (Hoboken, N.J.) · 2025Article
- Creb5 controls its own expression and directly induces the joint interzone regulatory program.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Restoring articular cartilage: insights from structure, composition and development.Nature reviews. Rheumatology · 2025Review
- PDGFRα signaling regulates cartilage and fibrous tissue differentiation during synovial joint development.Nature communications · 2025Article
- Stem and progenitor cells in the synovial joint as targets for regenerative therapy.Nature reviews. Rheumatology · 2025Review
- The methylomic landscape of human articular cartilage development contains epigenetic signatures of osteoarthritis risk.American journal of human genetics · 2024Article
- A conserved transcription factor regulatory program promotes tendon fate.Developmental cell · 2024Article
- Pre-hypertrophic chondrogenic enhancer landscape of limb and axial skeleton development.Nature communications · 2024Article
- Environmental and Genetic Risk Factors in Developmental Dysplasia of the Hip for Early Detection of the Affected Population.Diagnostics (Basel, Switzerland) · 2024Article
- Cis-regulatory control of mammalian Trps1 gene expression.Journal of experimental zoology. Part B, Molecular and developmental evolution · 2024Article
- Molecular mechanism of synovial joint site specification and induction in developing vertebrate limbs.Development (Cambridge, England) · 2023Article
- Genetic risk of osteoarthritis operates during human skeletogenesis.Human molecular genetics · 2023Article
- Spatiotemporal Characterization of Human Early Intervertebral Disc Formation at Single-Cell Resolution.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Taxonomy of fibroblasts and progenitors in the synovial joint at single-cell resolution.Annals of the rheumatic diseases · 2023Article
- Sox, Fox, and Lmx1b binding sites differentially regulate a Gdf5-Associated regulatory region during elbow development.Frontiers in cell and developmental biology · 2023Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 6 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.