Intraflagellar transport protein 122 antagonizes Sonic Hedgehog signaling and controls ciliary localization of pathway components
Intraflagellar transport protein 122 antagonizes Sonic Hedgehog signaling and controls ciliary localization of pathway components
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DOI：
10.1073/pnas.1011410108
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发表时间：
2011-01-25
影响因子：
11.1
通讯作者：
Eggenschwiler, Jonathan T.
中科院分区：
文献类型：
--
作者：
Qin, Jian;Lin, Yulian;Eggenschwiler, Jonathan T.
在哺乳动物中，初级纤毛是正常的Sonic Hedgehog(Shh)信号所必需的。然而，它们在信号转导过程中的作用仍不清楚。我们已经鉴定出开放脑姐妹基因(SopB)，它是小鼠鞭毛内转运蛋白122(Ift122)的一个零等位基因。IFT122在Shh配体和跨膜蛋白平滑的下游，但在Gli2转录因子的上游，负调控纤毛中的Shh途径。Ift122(SopB)突变体产生初生纤毛，但它们表现出有缺陷的逆行鞭毛内运输的特征。IFT122通过不同的方式控制Shh途径调节剂的纤毛定位。干扰IFT122导致Gli2和Gli3在纤毛尖端积累，同时阻止拮抗剂TULP3的纤毛定位。融合抑制因子和平滑抑制因子通过IFT122非依赖机制定位于纤毛。我们认为，纤毛顶端Shh通路的正负调节因子之间的平衡控制着该通路的输出，Shh信号通过鞭毛内转运来调节这种平衡。
Primary cilia are required for proper Sonic Hedgehog (Shh) signaling in mammals. However, their role in the signal transduction process remains unclear. We have identified sister of open brain (sopb), a null allele of mouse Intraflagellar transport protein 122 (Ift122). IFT122 negatively regulates the Shh pathway in the cilium at a step downstream of the Shh ligand and the transmembrane protein Smoothened, but upstream of the Gli2 transcription factor. Ift122(sopb) mutants generate primary cilia, but they show features of defective retrograde intraflagellar transport. IFT122 controls the ciliary localization of Shh pathway regulators in different ways. Disruption of IFT122 leads to accumulation of Gli2 and Gli3 at cilia tips while blocking the ciliary localization of the antagonist TULP3. Suppressor of Fused and Smoothened localize to the cilium through an IFT122-independent mechanism. We propose that the balance between positive and negative regulators of the Shh pathway at the cilium tip controls the output of the pathway and that Shh signaling regulates this balance through intraflagellar transport.