c-Jun is required for the specification of joint cell fates
c-Jun is required for the specification of joint cell fates
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DOI：
10.1101/gad.209239.112
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发表时间：
2013-03-01
影响因子：
10.5
通讯作者：
Tabin, Clifford J.
中科院分区：
文献类型：
--
作者：
Kan, Akinori;Tabin, Clifford J.
关节在发育中的骨骼内通过最初连续的软骨凝聚的分割和空化形成。然而，控制关节形成的分子途径在很大程度上仍有待澄清。特别是，虽然已经确定了几个关键的分泌信号，还没有转录因子被描述为在关节形成的早期阶段发挥作用。在早期关节标记Wnt 9a的上游工作，我们发现转录因子c-Jun在指定关节细胞命运中起着关键作用。我们首先在转基因报告小鼠中鉴定了驱动关节特异性表达的Wnt 9a基因上游的增强子。一个全面的计算机屏幕建议c-Jun作为一个候选转录因子激活这个Wnt 9a增强子元件。c-Jun在胚胎关节发育期间在关节中特异性表达，并且其从小鼠早期肢芽间充质中的条件性缺失严重影响所有肢关节的起始和随后的分化。c-Jun在关节发育的早期直接调节Wnt 16和Wnt 9a，导致关节间带中典型Wnt活性的降低。出生后，c-Jun缺陷小鼠表现出一系列关节异常，包括并列骨骼元素之间的软骨连续性、不规则关节面和韧带发育不全。
Joints form within the developing skeleton through the segmentation and cavitation of initially continuous cartilage condensations. However, the molecular pathways controlling joint formation largely remain to be clarified. In particular, while several critical secreted signals have been identified, no transcription factors have yet been described as acting in the early stages of joint formation. Working upstream of the early joint marker Wnt9a, we found that the transcription factor c-Jun plays a pivotal role in specifying joint cell fates. We first identified an enhancer upstream of the Wnt9a gene driving joint-specific expression in transgenic reporter mice. A comprehensive in silico screen suggested c-Jun as a candidate transcription factor activating this Wnt9a enhancer element. c-Jun is specifically expressed in joints during embryonic joint development, and its conditional deletion from early limb bud mesenchyme in mice severely affects both initiation and subsequent differentiation of all limb joints. c-Jun directly regulates Wnt16 as well as Wnt9a during early stages of joint development, causing a decrease of canonical Wnt activity in the joint interzone. Postnatally, c-Jun-deficient mice show a range of joint abnormalities, including cartilaginous continuities between juxtaposed skeletal elements, irregular articular surfaces, and hypoplasia of ligaments.