Ift88 regulates Hedgehog signaling, Sfrp5 expression, and β-catenin activity in post-natal growth plate.
Ift88 regulates Hedgehog signaling, Sfrp5 expression, and β-catenin activity in post-natal growth plate.
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DOI：
10.1002/jor.22237
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发表时间：
2013-03
影响因子：
2.8
通讯作者：
Serra, Rosa
中科院分区：
文献类型：
--
作者：
Chang, Ching-Fang;Serra, Rosa
初级纤毛存在于大多数细胞类型上，包括软骨细胞。初级纤毛功能障碍导致包括骨骼发育不良在内的多效性症状。以前，我们发现，删除Ift 88和随后的消耗初级纤毛从软骨细胞导致混乱的柱状结构和早期损失的生长板。为了了解Ift 88调节生长板功能的潜在机制，我们比较了正常和Ift 88缺失生长板中的基因表达谱。通路分析表明Hedgehog（Hh）信号通路是突变体生长板中受影响最大的通路。Wnt拮抗剂Sfrp 5的表达也下调。此外，Sfrp 5上调Shh在肋骨软骨细胞和调节Sfrp 5的Shh在突变体细胞减弱。该结果表明Sfrp 5是Hh的下游靶标，并且Ift 88调节其表达。Sfrp 5是Wnt信号传导的细胞外拮抗剂。我们观察到在Ift 88突变小鼠生长板的扁平柱状细胞中Wnt/β-连环蛋白信号传导的增加，如通过Axin 2和Lef 1的表达增加以及β-连环蛋白的核定位增加所测量的。我们认为，Ift 88和初级纤毛通过调节Ihh信号调节生长板中Sfrp 5和Wnt信号通路的表达。
Primary cilia are present on most cell types including chondrocytes. Dysfunction of primary cilia results in pleiotropic symptoms including skeletal dysplasia. Previously, we showed that deletion of Ift88 and subsequent depletion of primary cilia from chondrocytes resulted in disorganized columnar structure and early loss of growth plate. To understand underlying mechanisms whereby Ift88 regulates growth plate function, we compared gene expression profiles in normal and Ift88 deleted growth plates. Pathway analysis indicated that Hedgehog (Hh) signaling was the most affected pathway in mutant growth plate. Expression of the Wnt antagonist, Sfrp5, was also down-regulated. In addition, Sfrp5 was up-regulated by Shh in rib chondrocytes and regulation of Sfrp5 by Shh was attenuated in mutant cells. This result suggests Sfrp5 is a downstream target of Hh and that Ift88 regulates its expression. Sfrp5 is an extracellular antagonist of Wnt signaling. We observed an increase in Wnt/β-catenin signaling specifically in flat columnar cells of the growth plate in Ift88 mutant mice as measured by increased expression of Axin2 and Lef1 as well as increased nuclear localization of β-catenin. We propose that Ift88 and primary cilia regulate expression of Sfrp5 and Wnt signaling pathways in growth plate via regulation of Ihh signaling.
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