Transcription factor ERG and joint and articular cartilage formation during mouse limb and spine skeletogenesis
Transcription factor ERG and joint and articular cartilage formation during mouse limb and spine skeletogenesis
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DOI：
10.1016/j.ydbio.2007.01.037
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发表时间：
2007-05-01
影响因子：
2.7
通讯作者：
Pacifici, Maurizio
中科院分区：
文献类型：
--
作者：
Iwamoto, Masahiro;Tamamura, Yoshihiro;Pacifici, Maurizio
关节软骨和滑膜关节对于骨骼功能至关重要，但调节其发育的机制在很大程度上尚不清楚。在之前的研究中，我们发现ets转录因子ERG及其可变剪接变体C-1-1在雏鸡关节形成中发挥作用。在这里，我们将研究扩展到小鼠。我们发现ERG也在发育中的小鼠四肢关节中表达。为了测试 ERG 表达的调节，将涂有关节主调节蛋白 GDF-5 的珠子植入小鼠肢体外植体的早期关节附近；这导致了快速且强烈的异位 ERG 表达。我们克隆并表征了几种哺乳动物 ERG 变体，并使用 Col2al 基因启动子/增强子序列在转基因小鼠的软骨骨骼中表达了人类 C-1-1 对应物 (hERG3 Delta 81)。骨骼表型严重，新生儿致命，转基因小鼠比野生型同窝小鼠小，骨骼主要是软骨。肢体长骨原基完全由活跃表达胶原蛋白 IX 和聚集蛋白聚糖以及腱蛋白-C 等关节标记物的软骨细胞组成。不存在典型的生长板，并且成熟和肥大标记物的表达非常低，包括印度刺猬蛋白、X 胶原蛋白和 MMP-13。结果表明，ERG 是导致软骨细胞进入永久发育路径并成为关节形成细胞的分子机制的一部分，并且可能通过作用于 GDF-5 的下游来实现这一点。 (c) 2007 Elsevier Inc. 保留所有权利。
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.