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Abstract：
CEP104 is an evolutionarily conserved centrosomal and ciliary tip protein. CEP104 loss-of-function mutations are reported in patients with Joubert syndrome, but their function in the etiology of ciliopathies is poorly understood. Here, we show that cep104 silencing in zebrafish causes cilia-related manifestations: shortened cilia in Kupffer\'s vesicle, heart laterality, and cranial nerve development defects. We show that another Joubert syndrome-associated cilia tip protein, CSPP1, interacts with CEP104 at microtubules for the regulation of axoneme length. We demonstrate in human telomerase reverse transcriptase-immortalized retinal pigmented epithelium (hTERT-RPE1) cells that ciliary translocation of Smoothened in response to Hedgehog pathway stimulation is both CEP104 and CSPP1 dependent. However, CEP104 is not required for the ciliary recruitment of CSPP1, indicating that an intra-ciliary CEP104-CSPP1 complex controls axoneme length and Hedgehog signaling competence. Our in vivo and in vitro analyses of CEP104 define its interaction with CSPP1 as a requirement for the formation of Hedgehog signaling-competent cilia, defects that underlie Joubert syndrome.
摘要：
CEP104是进化上保守的中心体和纤毛尖端蛋白。据报道，Joubert综合征患者发生CEP104功能丧失突变，但是它们在纤毛病病因中的作用却知之甚少。这里,我们发现斑马鱼中的cep104沉默会导致纤毛相关表现：Kupffer\的囊泡中纤毛缩短，心脏偏侧，和颅神经发育缺陷。我们发现另一种与Joubert综合征相关的纤毛尖端蛋白，CSP1在微管处与CEP104相互作用，以调节轴突长度。我们证明了在人类端粒酶逆转录酶永生化的视网膜色素上皮（hTERT-RPE1）细胞中，响应于Hedgehog通路刺激的Smoothened纤毛易位是CEP104和CSP1依赖性的。然而,CSP1的纤毛募集不需要CEP104，这表明纤毛内CEP104-CSP1复合物控制轴突长度和Hedgehog信号传导能力。我们对CEP104的体内和体外分析将其与CSP1的相互作用定义为形成Hedgehog信号能力纤毛的要求，构成Joubert综合征的缺陷.
