Requirement for RAR-mediated gene repression in skeletal progenitor differentiation.
Requirement for RAR-mediated gene repression in skeletal progenitor differentiation.
复制标题
RAR介导的骨骼祖细胞分化中RAR介导的基因抑制的需求。
DOI：
10.1083/jcb.200112029
复制
发表时间：
2002-07-08
影响因子：
7.8
通讯作者：
Underhill, T Michael
中科院分区：
文献类型：
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作者：
Weston, Andrea D;Chandraratna, Roshantha A S;Torchia, Joseph;Underhill, T Michael
软骨形成是一个多步骤的过程，最终建立一个精确的模式化的骨形成模板。以前，我们确定了类维生素A受体介导的信号转导的损失是必要的和足够的表达成软骨细胞表型（。148：679-690）。在这里，我们证明了视黄酸受体（RAR）的活性和Sox 9，软骨形成所需的转录因子的转录活性之间的密切联系。具体而言，在小鼠肢体间充质的原代培养物中抑制RAR介导的信号传导导致Sox 9表达和活性增加。这种诱导减弱组蛋白去乙酰化酶抑制剂，抑制素A，并通过共表达的显性负核受体辅阻遏物-1，表明一个意想不到的要求RAR介导的抑制骨骼祖细胞分化。RAR活性的抑制导致p38丝裂原活化蛋白激酶（MAPK）和蛋白激酶A（PKA）途径的活化，表明它们在通过RAR抑制调节软骨形成中的潜在作用。因此，可通过激活p38 MAPK或PKA来挽救减弱分化的RAR信号传导的激活。总之，这些发现证明了主动RAR介导的基因抑制在软骨形成中的新作用，并建立了一个分层网络，其中RAR介导的信号传导在p38 MAPK和PKA信号传导途径上游发挥作用，以调节成软骨细胞表型的出现。
Chondrogenesis is a multistep process culminating in the establishment of a precisely patterned template for bone formation. Previously, we identified a loss in retinoid receptor–mediated signaling as being necessary and sufficient for expression of the chondroblast phenotype (. J. Cell Biol. 148:679–690). Here we demonstrate a close association between retinoic acid receptor (RAR) activity and the transcriptional activity of Sox9, a transcription factor required for cartilage formation. Specifically, inhibition of RAR-mediated signaling in primary cultures of mouse limb mesenchyme results in increased Sox9 expression and activity. This induction is attenuated by the histone deacetylase inhibitor, trichostatin A, and by coexpression of a dominant negative nuclear receptor corepressor-1, indicating an unexpected requirement for RAR-mediated repression in skeletal progenitor differentiation. Inhibition of RAR activity results in activation of the p38 mitogen-activated protein kinase (MAPK) and protein kinase A (PKA) pathways, indicating their potential role in the regulation of chondrogenesis by RAR repression. Accordingly, activation of RAR signaling, which attenuates differentiation, can be rescued by activation of p38 MAPK or PKA. In summary, these findings demonstrate a novel role for active RAR-mediated gene repression in chondrogenesis and establish a hierarchical network whereby RAR-mediated signaling functions upstream of the p38 MAPK and PKA signaling pathways to regulate emergence of the chondroblast phenotype.