A function for the Joubert syndrome protein Arl13b in ciliary membrane extension and ciliary length regulation
A function for the Joubert syndrome protein Arl13b in ciliary membrane extension and ciliary length regulation
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DOI：
10.1016/j.ydbio.2014.11.009
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发表时间：
2015-01-15
影响因子：
2.7
通讯作者：
Roy, Sudipto
中科院分区：
文献类型：
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作者：
Lu, Hao;Toh, Meng Tiak;Roy, Sudipto
纤毛在许多发育和生理环境中执行各种功能，并且与广泛的人类疾病的发病机制有关。虽然纤毛轴丝是通过鞭毛内运输组装的，但纤毛膜长度是如何调节的还不完全清楚。在这里，我们表明，斑马鱼胚胎以及哺乳动物细胞过表达的睫状膜蛋白Arl13b，一个ARF家族的小GTdR是必不可少的纤毛分化，纤毛长度显着增加。有趣的是，这种纤毛长度的增加是作为过表达的Arl13b的量的函数发生的。虽然Arl13b过表达过长的运动纤毛的运动性明显被破坏，但令人惊讶的是，异常长的不运动初级纤毛似乎保留了它们的信号传导能力。arl13 b由FoxJ1和Rfx诱导，当Arl13 b活性被抑制时，这些纤毛发生转录因子不能促进纤毛长度增加。相反，Arl13b的过表达足以恢复FoxJ1功能缺陷的斑马鱼胚胎的纤毛长度。我们发现，Arl13 b增加纤毛长度诱导突起的纤毛膜，然后由轴丝微管的延伸。使用突变版本的Arl13b，其中之一已被证明是睫状体病Joubert综合征的病因，我们建立的蛋白质的GTdR活性是必不可少的睫状体膜的延伸。综上所述，我们的研究结果确定Arl13 b作为一个重要的睫状膜生物发生和纤毛长度调节效应，并提供了深入了解Joubert综合征的蛋白质功能障碍的可能机制。(C)2014 Elsevier Inc. All rights reserved.
Cilia perform a variety of functions in a number of developmental and physiological contexts, and are implicated in the pathogenesis of a wide spectrum of human disorders. While the ciliary axoneme is assembled by intraflagellar transport, how ciliary membrane length is regulated is not completely understood. Here, we show that zebrafish embryos as well as mammalian cells overexpressing the ciliary membrane protein Arl13b, an ARF family small GTPase that is essential for ciliary differentiation, showed pronounced increase in ciliary length. Intriguingly, this increase in cilia length occurred as a function of the amounts of overexpressed Arl13b. While the motility of Arl13b overexpressing excessively long motile cilia was obviously disrupted, surprisingly, the abnormally long immotile primary cilia seemed to retain their signaling capacity. arl13b is induced by FoxJ1 and Rfx, and these ciliogenic transcription factors are unable to promote ciliary length increase when Arl13b activity is inhibited. Conversely, overexpression of Arl13b was sufficient to restore ciliary length in zebrafish embryos deficient in FoxJ1 function. We show that Arl13b increases cilia length by inducing protrusion of the ciliary membrane, which is then followed by the extension of the axonemal microtubules. Using mutant versions of Arl13b, one of which has been shown to be causative of the ciliopathy Joubert syndrome, we establish that the GTPase activity of the protein is essential for ciliary membrane extension. Taken together, our findings identify Arl13b as an important effector of ciliary membrane biogenesis and ciliary length regulation, and provide insights into possible mechanisms of dysfunction of the protein in Joubert syndrome. (C) 2014 Elsevier Inc. All rights reserved.