期刊
DEVELOPMENTAL BIOLOGY
卷 305, 期 1, 页码 40-51出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ydbio.2007.01.037
关键词
ERG transcription factor; articular chondrocytes; limb and spine skeletogenesis; GDF-5; extracellular matrix
资金
- NIAMS NIH HHS [R01 AR050507, R01 AR050507-03, R01 AR051007, R01 AR051007-02, AR050507, R01 AR046000-07, AR046000, R01 AR046000, AR051007, R01 AR056837] Funding Source: Medline
- NIA NIH HHS [R01 AG025868, R01 AG025868-02, AG025868] Funding Source: Medline
Articular cartilage and synovial joints are critical for skeletal function, but the mechanisms regulating their development are largely unknown. In previous studies we found that the ets transcription factor ERG and its alternatively-spliced variant C-1-1 have roles in joint formation in chick. Here, we extended our studies to mouse. We found that ERG is also expressed in developing mouse limb joints. To test regulation of ERG expression, beads coated with the joint master regulator protein GDF-5 were implanted close to incipient joints in mouse limb explants; this led to rapid and strong ectopic ERG expression. We cloned and characterized several mammalian ERG variants and expressed a human C-1-1 counterpart (hERG3 Delta 81) throughout the cartilaginous skeleton of transgenic mice, using Col2al gene promoter/enhancer sequences. The skeletal phenotype was severe and neonatal lethal, and the transgenic mice were smaller than wild type littermates and their skeletons were largely cartilaginous. Limb long bone anlagen were entirely composed of chondrocytes actively expressing collagen IX and aggrecan as well as articular markers such as tenascin-C. Typical growth plates were absent and there was very low expression of maturation and hypertrophy markers, including Indian hedgehog, collagen X and MMP-13. The results suggest that ERG is part of molecular mechanisms leading chondrocytes into a permanent developmental path and become joint forming cells, and may do so by acting downstream of GDF-5. (c) 2007 Elsevier Inc. All rights reserved.
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