In Vitro Modeling Using Ciliopathy-Patient-Derived Cells Reveals Distinct Cilia Dysfunctions Caused by CEP290 Mutations.
In Vitro Modeling Using Ciliopathy-Patient-Derived Cells Reveals Distinct Cilia Dysfunctions Caused by CEP290 Mutations.
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DOI：
10.1016/j.celrep.2017.06.045
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发表时间：
2017-07-11
期刊：
影响因子：
8.8
通讯作者：
Swaroop A
中科院分区：
文献类型：
--
作者：
Shimada H;Lu Q;Insinna-Kettenhofen C;Nagashima K;English MA;Semler EM;Mahgerefteh J;Cideciyan AV;Li T;Brooks BP;Gunay-Aygun M;Jacobson SG;Cogliati T;Westlake CJ;Swaroop A
CEP290是原生纤毛中的一种过渡区蛋白，它的突变会导致多种纤毛疾病，包括Leber先天性黑猩猩(LCA)和Joubert综合征相关疾病(JSRD)。我们在CEP290-LCA和CEP290-JSRD患者的细胞中检测了纤毛的生物发生和功能。CEP290蛋白在LCA成纤维细胞中减少，但对纤毛无明显影响；然而，CEP290-LCA患者的IPSCs来源的视杯显示较不发达的光感受器纤毛。JSRD成纤维细胞中CEP290缺失导致纤毛异常，纤毛生成减少。我们观察到ADCY3和Ar13b的选择性定位减少。值得注意的是，由于Smoothens和GPR161的纤毛运输增强，Hedgehog信号在CEP290-JSRD中得到增强。这些结果表明，成纤维细胞纤毛发生缺陷的程度(S)和光感受器分别与JSRD和LCA的表型严重程度直接相关，并加强了CEP290作为纤毛信号分子进出纤毛的选择性守门人的作用。使用来自CEP290突变患者的成纤维细胞和IPSC衍生的视杯，Shimada等人。在Leber先天性黑色素和Joubert综合征中，不同细胞类型的纤毛生成缺陷与临床严重程度之间显示出一致性。这些研究证实CEP290是初级纤毛内外信号分子的守门人。
Mutations in CEP290, a transition zone protein in primary cilia, cause diverse ciliopathies, including Leber congenital amaurosis (LCA) and Joubert syndrome related disorders (JSRD). We examined cilia biogenesis and function in cells derived from CEP290-LCA and CEP290-JSRD patients. CEP290 protein was reduced in LCA fibroblasts with no detectable impact on cilia; however, optic cups derived from iPSCs of CEP290-LCA patients displayed less-developed photoreceptor cilia. Lack of CEP290 in JSRD fibroblasts resulted in abnormal cilia and decreased ciliogenesis. We observed selectively reduced localization of ADCY3 and ARL13B. Notably, Hedgehog signaling was augmented in CEP290-JSRD because of enhanced ciliary transport of Smoothened and GPR161. These results demonstrate a direct correlation between the extent of ciliogenesis defect(s) in fibroblasts and photoreceptors with phenotypic severity in JSRD and LCA, respectively, and strengthen the role of CEP290 as a selective ciliary gatekeeper for transport of signaling molecules in and out of the cilium. Using fibroblasts and iPSC-derived optic cups from patients with distinct CEP290 mutations, Shimada et al. show a concordance between ciliogenesis defects in different cell types and clinical severity in Leber congenital amaurosis and Joubert syndrome. These studies establish CEP290 as gatekeeper of signaling molecules in and out of the primary cilium.
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影响因子：
14.8
作者：
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影响因子：
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作者：
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DOI：
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发表时间：
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期刊：
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