衣藻、纤毛与“纤毛相关疾病”

纤毛或鞭毛（两个名称在本文互为通用）是以细胞微管为核心而组装形成的一种细胞器官．运动纤毛在细胞运动中起的作用是显而易见的,比如精子的运动：近年来发现,曾被认为是退化器官的不动原生纤毛在动物发育和各种生理器官的正常生理活动中起着重要作用．原生纤毛具有调控细胞分裂,Hedgehog信号通路,非经典Wnt信号通路及钙信号传导等的作用．纤毛及其附属结构在结构或功能上的缺陷会导致多种多样的疾病,总称为“纤毛相关疾病”,包括男性不育症、呼吸道疾病（如不动纤毛综合征、肾囊肿、失明、多指（趾）症、内脏转位、肥胖症、高血压乃至精神发育迟滞等．纤毛在结构和功能上是非常保守的,我们目前对纤毛的结构与功能的认识和对“纤毛相关疾病”发生机理的了解主要来自于对各种模式生物的研究,其中包括具有研究优势的模式生物——雷氏衣藻（Chlamydomonas reinhardtii,一种单细胞绿萍）．对纤毛的进一步研究将深化人们对“纤毛相关疾病”的认识、促进对它的诊断、预防和治疗．本文对衣藻、纤毛及“纤毛相关疾病”的研究进展作一简短概述．     

初级纤毛与Wnt信号通路相关性研究进展

初级纤毛是一类以微管为基础结构的细胞器,其来源于细胞的母中心粒,锚定在细胞膜并如“天线”般突出细胞表面。作为细胞感受器,初级纤毛从环境中接受各种信号,传导至细胞内引起细胞反应。近期的研究表明,初级纤毛对与胚胎发育密切相关的Wnt信号通路的传导起重要作用。纤毛的损害可造成Wnt信号通路的异常,并引起胚胎中多类脏器一系列的病理改变,导致初级纤毛相关疾病的发生。文章主要阐述了初级纤毛与Wnt/β-catenin、Wnt/PCP通路及初级纤毛相关疾病之间的关系,并对初级纤毛相关疾病的治疗进行了初步探讨。对初级纤毛与Wnt信号通路关系的深入研究将有助于人们对该类疾病的进一步诊断和治疗。     

哺乳动物纤毛/鞭毛内运输在精子形成中的作用及机制研究进展

纤毛/鞭毛是真核生物细胞表面伸出的进化保守的细胞器,独特的位置和特性使它们在细胞运动和信号传递等生命过程发挥重要作用。哺乳动物纤毛/鞭毛的组装和维持都依赖纤毛/鞭毛内运输(intraflagellar transport,IFT)。IFT是由IFT复合体A和复合体B在驱动蛋白或马达蛋白驱动下的双向运输系统。该过程可将货物蛋白在胞体的合成位点与纤毛/鞭毛尖端的装配位点之间进行运输。鞭毛是哺乳动物精子产生动力的特异性细胞器,其完整性对精子正常功能至关重要。近年来研究表明,IFT在哺乳动物精子鞭毛形成和雄性生殖能力方面必不可少。本文对参与IFT的蛋白在精子鞭毛形成中的作用和机制进行了综述,以探讨其在男性不育症中的发病机制,为不育症的诊断和治疗提供理论基础。     

纤毛疾病和与之相关的基因

近年来,研究发现纤毛在生成或者形态的缺陷均能导致新生儿遗传性疾病。与其他细胞器不同的是,纤毛这一小的毛发状细胞器能在几乎所有的极性细胞表面上生成,而且功能非常多样化。纤毛在调节脊椎动物的发育和内环境的平衡起着相当重要的作用,而与纤毛相关基因的缺失则与一系列疾病相关,包括:Nephronophthisis、Joubert综合症、Meckel-Gruber综合症和BardetBiedl综合症等。结合最近的研究,本文主要对四类主纤毛相关疾病的基因进行归类总结。     

线粒体拟核结构及相关疾病研究进展

线粒体DNA(mitochondrial DNA,mtDNA)与一系列蛋白质相互作用形成核蛋白复合体,并包装折叠成类似原核生物拟核的结构,称为线粒体拟核(mitochondrial nucleoid)。参与线粒体拟核组成的相关蛋白包括线粒体转录因子、线粒体单链DNA结合蛋白以及多种参与线粒体中代谢途径的多功能蛋白。线粒体拟核结构的阐明对于进一步研究线粒体形态与功能以及mtDNA的遗传模式、基因表达调控具有重要意义。本文综述了线粒体拟核结构的最新研究进展,着重介绍组成拟核结构的重要蛋白,以及这些蛋白如何将mtDNA与柠檬酸循环等线粒体重要代谢途径相联系。同时,拟核相关蛋白(nucleoid-associated protein)的异常涉及多种人类疾病,这为研究线粒体相关疾病提供了新的思路。     

自噬对血管功能的影响及与相关疾病的关联研究进展

自噬(autophagy)是细胞利用溶酶体降解自身受损的细胞器和大分子物质的过程,在稳定细胞内环境中发挥着重要作用．研究发现,自噬影响血管功能,与血管疾病的病理生理进程密切相关．本文从自噬对血管功能的影响,与血管相关疾病(如动脉粥样硬化、腹主动脉瘤、肺动脉高压、糖尿病血管并发症等)的关系及药物对血管壁细胞自噬的调控进行综述,希望从自噬的角度来了解血管的功能和病变及一些疾病的发生发展进程,为治疗血管相关疾病提供新的思路．     

纤毛膜脂与纤毛病

纤毛是一类突出于细胞表面的主要由微管组成的有膜细胞器。纤毛由纤毛膜、基质、过渡区和轴丝组成,在细胞运动、环境信号感知和多细胞生物发育中发挥着重要作用。纤毛膜位于纤毛的最外层,是纤毛接触细胞外信号的第一场所。纤毛膜与细胞质膜相连却具有独特的脂质构成,其中,磷脂酰肌醇、神经酰胺和脂质筏结构等特殊脂类在纤毛形态维持和生理功能中发挥重要作用,主要参与纤毛中关键信号蛋白的正确定位及纤毛正常摆动。纤毛膜脂质组成发生异常是引发纤毛病的诱因之一,在巴德毕德氏综合征、朱伯特综合征、眼脑肾综合征中纤毛脂类和脂蛋白定位通常发生改变。该综述汇总了纤毛膜脂质成分的最新研究结果,探讨了脂质成分在纤毛中的功能,并介绍了脂类成分异常与纤毛病发生的联系,以期为解析纤毛病的分子机制提供思路。     

神经细胞初级纤毛在中枢神经系统疾病中作用的研究进展

初级纤毛广泛存在于哺乳动物中枢神经系统中,是神经细胞重要的胞外细胞器。初级纤毛中含有多种离子通道、G蛋白耦联受体、激酶等,提示初级纤毛可感受胞外信号并将信号转导至细胞内,从而引起细胞对外界刺激信号产生应答反应。近年来大量研究表明调控纤毛结构及功能的基因发生突变后,会导致许多单基因的遗传性疾病。当神经细胞初级纤毛中激酶、G蛋白耦联受体以及离子通道的功能异常后,往往会引起一系列的神经精神疾病、神经系统发育异常等神经系统疾病。本文就初级纤毛在神经系统疾病中作用的研究进展进行综述。     

BAFF及相关疾病

BAFF是TNF超家族的一个新成员,属Ⅱ型跨膜蛋白,由285个氨基酸组成,通过与其受体结合而广泛参与B、T淋巴细胞增殖和功能的调节。BAFF缺乏可导致免疫功能低下,过表达则与多种自身免疫性疾病的发生和发展密切相关,BAFF可能还与某些肿瘤的发生有关。以BAFF及受体为作用靶点,可以设计治疗相关疾病的新策略。     

结缔组织生长因子与相关疾病的研究进展

结缔组织生长因子是具有多种生物学活性的细胞因子,与细胞增殖、分化、凋亡、粘附、胚胎发育及伤口愈合等过程有关,近年来发现,在硬皮病、动脉粥样硬化、系统性硬化症和一些良恶性肿瘤等多种疾病中,结缔组织生长因子的表达水平出现了不同程度的升高或降低,与疾病的发生、发展关系密切。     

Cytoplasmic dynein-2: from molecules to human diseases

The dynein motor protein family is involved in a wide variety of functions in eukaryotic cells. The axonemal dynein class and cytoplasmic dynein-1 subclass have been well characterized. However, the cytoplasmic dynein-2 subclass of the family has only recently begun to be understood. We describe the entire dynein family but focus on cytoplasmic dynein-2. Dynein-2 consists of a heavy, an intermediate, a light intermediate, and a light chain. The complex appears to function primarily as the retrograde motor for intraflagellar transport. This process is important for the formation and maintenance of cilia and flagella. Additionally, dynein-2 has roles in the control of ciliary length and in non-ciliary functions. Mutations in the human dynein-2 heavy chain lead to cilia-related diseases.     

How do cilia organize signalling cascades?

Cilia and flagella are closely related centriole-nucleated protrusions of the cell with roles in motility and signal transduction. Two of the best-studied signalling pathways organized by cilia are the transduction cascade for the morphogen Hedgehog in vertebrates and the mating pathway that initiates gamete fusion in the unicellular green alga Chlamydomonas reinhardtii. What is the role of cilia in these signalling transduction cascades? In both Hedgehog and mating pathways, all signalling intermediates have been found to localize to cilia, and, for some signalling factors, ciliary localization is regulated by pathway activation. Given a concentration factor of three orders of magnitude provided by translocating a protein into the cilium, the compartment model proposes that cilia act as miniaturized reaction tubes bringing signalling factors and processing enzymes in close proximity. On the other hand, the scaffolding model views the intraflagellar transport machinery, whose primary function is to build cilia and flagella, as a molecular scaffold for the mating transduction cascade at the flagellar membrane. While these models may coexist, it is hoped that a precise understanding of the mechanisms that govern signalling inside cilia will provide a satisfying answer to the question ‘how do cilia organize signalling?’. This review covers the evidence supporting each model of signalling and outlines future directions that may address which model applies in given biological settings.     

Defective flagellar assembly and length regulation in LF3 null mutants in Chlamydomonas

Four long-flagella (LF) genes are important for flagellar length control in Chlamydomonas reinhardtii. Here, we characterize two new null lf3 mutants whose phenotypes are different from previously identified lf3 mutants. These null mutants have unequal-length flagella that assemble more slowly than wild-type flagella, though their flagella can also reach abnormally long lengths. Prominent bulges are found at the distal ends of short, long, and regenerating flagella of these mutants. Analysis of the flagella by electron and immunofluorescence microscopy and by Western blots revealed that the bulges contain intraflagellar transport complexes, a defect reported previously (for review see Cole, D.G., 2003. Traffic. 4:435-442) in a subset of mutants defective in intraflagellar transport. We have cloned the wild-type LF3 gene and characterized a hypomorphic mutant allele of LF3. LF3p is a novel protein located predominantly in the cell body. It cosediments with the product of the LF1 gene in sucrose density gradients, indicating that these proteins may form a functional complex to regulate flagellar length and assembly.     

Ciliary Length Sensing Regulates IFT Entry via Changes in FLA8/KIF3B Phosphorylation to Control Ciliary Assembly

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The intraflagellar transport machinery of Chlamydomonas reinhardtii

First discovered in the green alga, Chlamydomonas , intraflagellar transport (IFT) is the bidirectional movement of protein particles along the length of eukaryotic cilia and flagella. Composed of ∼16 different proteins, IFT particles are moved out to the distal tip of the organelle by kinesin-II and are brought back to the cell body by cytoplasmic dynein 1b. Mutant analysis of the IFT motor and particle proteins using diverse organisms has revealed a conserved and essential role for IFT in the assembly and maintenance of cilia and flagella. IFT is thought to mediate this assembly through the delivery of axonemal precursors out to the distal tip of the growing organelle. Consistent with this model, the IFT particle proteins are rich in protein–protein binding motifs, suggesting that the particles may act as scaffolds for the binding of multiple cargoes. With most of the IFT proteins now identified at the level of the gene, this review will briefly examine both the structure and function of the IFT machinery of Chlamydomonas reinhardtii .     

Cloning and characterization of the human IFT20 gene*

Intraflagellar transport (IFT), in which molecular motors and IFT particle proteins participate, is very important in assembling and maintaining many cilia/flagella, such as the motile cilia that drive the swimming of cells and embryos, the nodal cilia that generate left-right asymmetry in vertebrate embryos, and the sensory cilia that detect sensory stimuli in some animals. Here we report the molecular cloning and characterization of a novel human cDNA that is 1060 base pair in length, encoding a putative protein of 158 amino acid residues which shares high homology to Mus musculus intraflagellar transport protein mIFT20 (Accession number AAL99202, identity 82.3%, similarity 82.9%) at protein level. Bioinformatics analysis revealed that the gene is composed of 6 exons and is located on human chromosome 17p11.1. RT-PCR showed that this gene is expressed in human brain, lung, kidney and pancreas, and lower expression were also detected in human placenta, liver, thymus, prostate and testis.