Duldulao Neil A, Lee Sunjin, Sun Zhaoxia
Department of Genetics, Yale University School of Medicine, 333 Cedar Street, NSB-393, New Haven, CT 06520, USA.
Development. 2009 Dec;136(23):4033-42. doi: 10.1242/dev.036350.
arl13b was initially cloned as the novel cystic kidney gene scorpion (sco) in zebrafish and was shown to be required for cilia formation in the kidney duct. In mouse, a null mutant of Arl13b shows abnormal ultrastructure of the cilium and defective sonic hedgehog (Shh) signaling. Importantly, a recent study linked mutations in ARL13B to a classical form of Joubert syndrome (JS), an autosomal recessive disorder characterized by a distinctive cerebellar malformation. In this study, we analyzed the zebrafish arl13b (sco) mutant and gene products in detail. We first demonstrate that Arl13b is a protein that is highly enriched in the cilium and is required for cilia formation in multiple organs in zebrafish, and that knockdown of arl13b leads to multiple cilia-associated phenotypes. We additionally show that multiple regions of Arl13b are required for its localization to the cilium. By means of rescuing experiments with a series of deletion and point mutants, we further demonstrate that the ciliary localization is crucial for the in vivo function of Arl13b. Together, these results strongly support the hypothesis that JS-related disease (JSRD) is a ciliopathy, or a disease caused by ciliary defects, and that Arl13b functions mainly through the cilium.
arl13b最初是作为斑马鱼中新型多囊肾基因蝎子（sco）被克隆出来的，并且已证明它是肾管纤毛形成所必需的。在小鼠中，Arl13b的无效突变体显示出纤毛的超微结构异常以及音猬因子（Shh）信号传导缺陷。重要的是，最近的一项研究将ARL13B中的突变与一种典型的乔伯特综合征（JS）联系起来，乔伯特综合征是一种常染色体隐性疾病，其特征为独特的小脑畸形。在本研究中，我们详细分析了斑马鱼arl13b（sco）突变体及其基因产物。我们首先证明，Arl13b是一种在纤毛中高度富集的蛋白质，是斑马鱼多个器官中纤毛形成所必需的，并且敲低arl13b会导致多种与纤毛相关的表型。我们还表明，Arl13b的多个区域对于其定位于纤毛是必需的。通过用一系列缺失和点突变体进行拯救实验，我们进一步证明纤毛定位对于Arl13b的体内功能至关重要。总之，这些结果有力地支持了以下假设：与乔伯特综合征相关的疾病（JSRD）是一种纤毛病，即由纤毛缺陷引起的疾病，并且Arl13b主要通过纤毛发挥作用。
