Primary cilia control hedgehog signaling during muscle differentiation and are deregulated in rhabdomyosarcoma
Primary cilia control hedgehog signaling during muscle differentiation and are deregulated in rhabdomyosarcoma
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DOI：
10.1073/pnas.1323265111
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发表时间：
2014-06-24
影响因子：
11.1
通讯作者：
Dynlacht, Brian David
中科院分区：
文献类型：
--
作者：
Fu, Wenxiang;Asp, Patrik;Dynlacht, Brian David
初级纤毛起细胞天线的作用，传递不同的信号通路，最近的证据表明初级纤毛在发育和癌症中起重要作用。然而，纤毛在正常肌肉发育和横纹肌肉瘤(RMS)中的作用尚未被探索。在这里，我们认为初级纤毛与骨骼肌细胞的增殖、刺猬(HH)信号和分化有关。纤毛和HH信号在成肌细胞分化过程中高度动态。我们发现纤毛在成肌分化的初始阶段被组装，但随着细胞在成肌过程中的进展而消失，伴随着对纤毛组装至关重要的蛋白质的破坏，并在HH效应器Gli3离开纤毛后不久。重要的是，我们表明，初级纤毛的消融强烈抑制了HH信号和肌源性分化，同时促进了增殖。有趣的是，我们的数据进一步表明，纤毛组装和HH信号在RMS中都被解除调控，在RMS细胞的某些亚群中纤毛对HH配体做出反应，但在其他亚群中不起作用。总之，这些发现为初级纤毛组装和分解在控制HH信号和肌肉细胞早期分化中的重要作用提供了证据。我们认为，中心体和纤毛蛋白的临时协调破坏是肌源性分化过程中去除初级纤毛和停止HH信号的必要前提。此外，我们的结果进一步将RMS群体分层，并强调纤毛组装和拆卸是潜在的RMS药物靶点。
The primary cilium acts as a cellular antenna, transducing diverse signaling pathways, and recent evidence suggests that primary cilia are important in development and cancer. However, a role for cilia in normal muscle development and rhabdomyosarcoma (RMS) has not been explored. Here we implicate primary cilia in proliferation, hedgehog (Hh) signaling, and differentiation of skeletal muscle cells. Cilia and Hh signaling are highly dynamic during the differentiation of myoblasts. We show that cilia are assembled during the initial stages of myogenic differentiation but disappear as cells progress through myogenesis, concomitant with the destruction of proteins critical for cilia assembly and shortly after the Hh effector, Gli3, leaves the cilium. Importantly, we show that ablation of primary cilia strongly suppresses Hh signaling and myogenic differentiation while enhancing proliferation. Interestingly, our data further indicate that both cilia assembly and Hh signaling are deregulated in RMS, and cilia respond to Hh ligand in certain subsets of RMS cells but not others. Together, these findings provide evidence for an essential role for both primary cilia assembly and disassembly in the control of Hh signaling and early differentiation in muscle cells. We suggest that the temporally orchestrated destruction of centrosomal and ciliary proteins is a necessary antecedent for removal of the primary cilium and cessation of Hh signaling during myogenic differentiation. Additionally, our results further stratify RMS populations and highlight cilia assembly and disassembly as potential RMS drug targets.