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 language | English (US) |
|---|---|
| Article number | e1006454 |
| Journal | PLoS Genetics |
| Volume | 12 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 1 2016 |
Fingerprint
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 journal › Article
}
TY - JOUR
T1 - Heads, Shoulders, Elbows, Knees, and Toes
T2 - Modular Gdf5 Enhancers Control Different Joints in the Vertebrate Skeleton
AU - Chen, Hao
AU - Capellini, Terence D.
AU - Schoor, Michael
AU - Mortlock, Doug P.
AU - Reddi, A Hari
AU - Kingsley, David M.
PY - 2016/11/1
Y1 - 2016/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85000624431&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85000624431&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1006454
DO - 10.1371/journal.pgen.1006454
M3 - Article
C2 - 27902701
AN - SCOPUS:85000624431
VL - 12
JO - PLoS Genetics
JF - PLoS Genetics
SN - 1553-7390
IS - 11
M1 - e1006454
ER -