Heads, Shoulders, Elbows, Knees, and Toes: Modular Gdf5 Enhancers Control Different Joints in the Vertebrate Skeleton

Hao Chen, Terence D. Capellini, Michael Schoor, Doug P. Mortlock, A Hari Reddi, David M. Kingsley

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1006454
JournalPLoS Genetics
Volume12
Issue number11
DOIs
StatePublished - Nov 1 2016

Fingerprint

Growth Differentiation Factor 5
elbows
knees
Toes
Elbow
shoulders
Skeleton
joints (animal)
skeleton
Vertebrates
Knee
vertebrate
Joints
vertebrates
osteoarthritis
Osteoarthritis
mice
Locus Control Region
locomotion
regulator genes

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Heads, Shoulders, Elbows, Knees, and Toes : Modular Gdf5 Enhancers Control Different Joints in the Vertebrate Skeleton. / Chen, Hao; Capellini, Terence D.; Schoor, Michael; Mortlock, Doug P.; Reddi, A Hari; Kingsley, David M.

In: PLoS Genetics, Vol. 12, No. 11, e1006454, 01.11.2016.

Research output: Contribution to journalArticle

Chen, Hao ; Capellini, Terence D. ; Schoor, Michael ; Mortlock, Doug P. ; Reddi, A Hari ; Kingsley, David M. / Heads, Shoulders, Elbows, Knees, and Toes : Modular Gdf5 Enhancers Control Different Joints in the Vertebrate Skeleton. In: PLoS Genetics. 2016 ; Vol. 12, No. 11.
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