Negative regulation of ciliary length by ciliary male germ cell-associated kinase (Mak) is required for retinal photoreceptor survival
Negative regulation of ciliary length by ciliary male germ cell-associated kinase (Mak) is required for retinal photoreceptor survival
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DOI：
10.1073/pnas.1009437108
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发表时间：
2010-12-28
影响因子：
11.1
通讯作者：
Furukawa, Takahisa
中科院分区：
文献类型：
--
作者：
Omori, Yoshihiro;Chaya, Taro;Furukawa, Takahisa
纤毛在许多器官中起着细胞传感器的作用，它们的疾病被称为“纤毛病”。“虽然睫状体成分和运输机制已经得到了很好的研究，但对睫状体形成和维持的调节机制知之甚少。在这里，我们表明，男性生殖细胞相关激酶（Mak）调节视网膜光感受器纤毛长度和亚区室化。Mak定位于感光细胞的连接纤毛和外节轴丝。在Mak-null视网膜中，光感受器表现出细长的纤毛和进行性变性。我们观察到鞭毛内转运88（IFT 88）和IFT 57的积累，驱动蛋白家族成员3A（Kif 3a）的扩增，以及Mak-null光感受器纤毛中乙酰化α-微管蛋白信号。我们发现异常的视紫红质积累在Mak-null感光细胞体在出生后第14天。此外，过度表达视网膜色素变性1（RP 1），微管相关蛋白定位于外段轴丝，诱导纤毛伸长，和Mak共表达救出过度纤毛伸长RP 1。RP 1 N-末端部分诱导细胞中纤毛伸长和乙酰化α-微管蛋白标记的强度增加，并被Mak磷酸化。这些结果表明，Mak是必不可少的纤毛长度的调节和所需的长期生存的光感受器。
Cilia function as cell sensors in many organs, and their disorders are referred to as "ciliopathies." Although ciliary components and transport machinery have been well studied, regulatory mechanisms of ciliary formation and maintenance are poorly understood. Here we show that male germ cell-associated kinase (Mak) regulates retinal photoreceptor ciliary length and subcompartmentalization. Mak was localized both in the connecting cilia and outer-segment axonemes of photoreceptor cells. In the Mak-null retina, photoreceptors exhibit elongated cilia and progressive degeneration. We observed accumulation of intraflagellar transport 88 (IFT88) and IFT57, expansion of kinesin family member 3A (Kif3a), and acetylated alpha-tubulin signals in the Mak-null photoreceptor cilia. We found abnormal rhodopsin accumulation in the Mak-null photoreceptor cell bodies at postnatal day 14. In addition, overexpression of retinitis pigmentosa 1 (RP1), a microtubule-associated protein localized in outer-segment axonemes, induced ciliary elongation, and Mak coexpression rescued excessive ciliary elongation by RP1. The RP1 N-terminal portion induces ciliary elongation and increased intensity of acetylated a-tubulin labeling in the cells and is phosphorylated by Mak. These results suggest that Mak is essential for the regulation of ciliary length and is required for the long-term survival of photoreceptors.