CEP290在纤毛发生起始过程中的作用及机制研究

纤毛在人体细胞中普遍存在，在细胞运动、信号感知和传递中发挥重要作用，其功能缺陷可导致许多人类遗传疾病。但目前我们对纤毛发生是如何起始的仍知之甚少。CEP290是一个进化保守的纤毛过渡区(Transition zone)蛋白，其突变会导致多种纤毛病。已知CEP290的主要功能是组装纤毛过渡区。我们在前期研究中，用CRISPR/Cas9技术获得了一个果蝇CEP290的完全缺失突变体，惊奇地发现，CEP290是果蝇纤毛发生起始所必需的。进一步研究发现，DZIP1是CEP290调控纤毛发生起始的下游关键蛋白。我们推测CEP290招募DZIP1，DZIP1随后促进早期纤毛膜的形成从而起始纤毛发生。本项目将利用果蝇模式的遗传优势，重点研究CEP290和DZIP1在纤毛发生起始过程中的作用及机制。我们的研究将有助于解析CEP290的新功能，为揭示纤毛形成的分子机制和人类纤毛病机理做出贡献。

Cilia are antenna-like organelles which found in most human cells and play important roles in cell movement, signal perception and transmission. Dysfunction of cilia leads to many human genetic diseases. However, we know little about ciliogenesis initiation. CEP290 is an evolutionarily conserved protein localized to the ciliary transition zone, and its mutation leads to a variety of ciliopathies. It is well known that CEP290 is required for the function and formation of transition zone. We obtained a Drosophila cep290 null mutant using CRISPR/Cas9 technique. Interestingly, we found that CEP290 is essential for ciliogenesis initiation. Further study showed that DZIP1 is the downstream key protein of CEP290 regulating cilogenesis initiation. We proposed that CEP290 recruits DZIP1, which then promotes early ciliary membrane formation and ciliogenesis initiation. In this application, we will aim to dissect the function and mechanism of CEP290 and DZIP1 in ciliogenesis initiation. Our proposed studies will uncover a previously uncharacterized important function of CEP290 in ciliogenesis initiation, and will shed light on our understanding of the mechanism of ciliogenesis and the pathogenesis of CEP290 related disease.