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糖基化对斑马鱼发育及再生作用的研究进展
贾丽苑, 冯娟涛, 崔继红     
西北大学生命科学学院组织工程实验室,西安 710069
摘要: 对有机体发育和再生的研究一直是生命科学领域探索热点之一,斑马鱼由于具有发育速度快、胚胎透明便于观察以及其尾鳍、心脏、神经系统等组织器官可以再生等众多优点,已经成为应用最为广泛的模式生物之一.在斑马鱼发育及再生过程中,细胞发生增殖、分化、形态建成等代谢活动,而对其中调控机制的研究尚未完全明确,对其深入探究的意义不言而喻,可以为很多疾病的认识治疗、组织工程的发展奠定理论基础.研究已经表明,在此过程中,有很多蛋白质参与发育及再生的调节,而蛋白质糖基化是重要的蛋白质翻译后修饰,糖基化的变化会影响细胞识别、黏附、信号传导等,从而导致炎症、肿瘤等恶性疾病的发生.近年来,糖组学的发展为发育生物学和再生医学提供了新的思路和研究成果,本文就糖基化变化在斑马鱼的发育过程中发挥的作用做一综述,并对今后它对再生过程的作用进行展望.
关键词: 斑马鱼     糖基化     发育     再生    
Glycosylation Related to The Development and Regeneration of Zebrafish
JIA Li-Yuan, FENG Juan-Tao, CUI Ji-Hong     
Laboragy of Tissue Engineering, College of Life Sciences, Northwest University, Xi′an 710069, China
*This work was supported by a grant from The National Natural Science Foundation of China(31771055)
** Corresponding author: CUI Ji-Hong, Tel: 86-29-88302411, E-mail: cjh@nwu.edu.cn
Received: September 18, 2017 Accepted: September 26, 2017
Abstract: The study on tissue development and regeneration is one of the hot spots of life science. Zebrafish has become one of the popular model organisms due to its rapid growth rate, transparent embryos which is easy to observe, and the capacity to regenerate fin, heart, nervous system, etc. During the development and regeneration process of zebrafish, cell proliferation, differentiation, morphogenesis and other metabolic activities occurs, but little is known about the regulatory mechanism among such complex dynamic processes to us. Further studies on these processes have magnificent meanings, for instance, laying a theoretical foundation for the treatment of many diseases, and also promoting the progress of tissue engineering. Previous study has shown that multifold proteins involved in the regulation of tissue development and regeneration. Protein glycosylation is an important post-translational modification, which can affect cell recognition, adhesion, and signal transduction, even lead to inflammation, cancer and other malignant diseases. In recent years, the development of glycomics provides new ideas for developmental biology and regenerative medicine. In this present review, we summarize the role of glycosylation alteration in the development process of zebrafish, and prospect for its future study on regeneration.
Key words: words zebrafish     glycosylation     development     regeneration    

斑马鱼(Danio rerio)属于热带鱼类,是一种小型脊椎动物.20世纪70年代,Streisinger等[1-2]首次将斑马鱼作为生命科学领域的模式生物,应用于脊椎动物的遗传学和发育生物学研究,基于斑马鱼具有使用成本低,可以大量繁殖,发育速度快,便于观察表型和进行遗传操作(正向遗传和反向遗传),对诱变敏感,有相对小的基因组等优点,它已经成为了目前应用最广泛的模式生物之一.研究者们已经揭示了很多在斑马鱼的发育及再生过程中关键事件和影响因子,例如从胚芽层的形成到分化出各种组织器官[3-4].目前,斑马鱼在生物行为学、干细胞和相关疾病模型的研究也是我们关注的热点[5-8].

糖基化是蛋白质的翻译后修饰,它在细胞和机体内具有重要的生物学作用[9-10].蛋白质糖基化是由不同糖基转移酶介导完成的,它将不同的糖链转移至蛋白质或脂质的氨基酸残基上形成糖苷键.糖基化过程发生在内质网、高尔基体、细胞质或细胞核上,大多分泌蛋白和细胞表面蛋白的翻译后修饰都是通过糖基化实现的,包括酪氨酸激酶受体、整合素[11]等.这些聚糖结构在生物学功能中有非常重要的作用[12],它影响细胞的分化、识别、黏附,糖基化的变化会快速改变细胞信号通路,糖基化异常往往会导致疾病的发生[13-16].目前已经有超过50%的蛋白质被证明是糖基化蛋白,而大部分分泌蛋白都是糖蛋白,它们参与宿主-病原体反应、肿瘤的侵袭转移等过程[17].越来越多的研究者开始倾向于研究不同种类的糖基化在斑马鱼的组织和器官发育及再生过程中发挥的作用,将糖组学应用于该领域,将会对糖基化在发育过程的调节机制有更深入透彻的理解,也会为相关疾病的发病机制、治疗及预后奠定理论基础.

1 斑马鱼是生物研究良好的模式生物

斑马鱼的基因组与人类基因组有70%的相似性,与已知的人类疾病基因有80%以上同源性,包括癌基因和抑癌基因[18].斑马鱼繁殖力高,交配后每周能够生产200~300个受精卵,胚胎可在体外发育迅速,从受精卵到自主游动的幼虫只需短短几天时间,其消化系统、神经系统和心血管器官系统在一周以内发育完成[19-22],3个月左右达到性成熟,在发育的最初几周内是光学透明的,可以直观地通过光镜和荧光显微镜直接观察其肝脏、大脑、脊柱等器官发生和形态分化等过程.由于它们与人类在遗传和生理学方面的高度相似性,通过化学疗法[23]、基因敲除[24]、基因过表达[25]和异种移植[26]等手段,可以快速建立稳定的转基因或突变斑马鱼系,或者某种疾病发生模型,并可利用活体成像、荧光蛋白标记和细胞追踪技术等实时监测癌症扩散、肿瘤生成、转移和侵袭等现象,深入研究其中的生理病理机制.目前斑马鱼已被用于多种类型疾病的研究,如糖尿病、多囊肾病、肌营养不良[20, 27-30]以及多种癌症,如皮肤癌[24-25]、胰腺癌、乳腺癌[26, 31]、白血病[32]、胶质瘤[33]与肺癌[34]等.此外,斑马鱼还可以作为一种极有效率的高通量筛选工具[35-38],同时从化学和基因角度,对疾病发生的潜在基因和通路进行大规模筛查,也可将化合物、药物或小分子添加到斑马鱼的水环境中[39],斑马鱼胚已应用于新药品投入使用前的表型筛选[35, 40].

器官的再生是一种重要的生物现象,斑马鱼的中央及周围神经系统、心脏、肾脏、尾鳍等器官组织都可以完成再生,这些器官在损伤后可以迅速恢复为原有大小和形态,因其独特的生理优势,成为再生医学的实验模式动物[41-45].与斑马鱼相比,人类并不具备断肢等其他组织器官的再生能力,目前我们对斑马鱼的再生机理了解十分有限,运用现代生物学手段,从细胞和分子角度去诠释组织器官的再生机制,以期促进人类再生医学的发展.不论是发育还是再生的过程,都会涉及到干细胞/祖细胞的激活、细胞的增殖、分化等调控过程,深入了解其中调控的分子机制都是非常必要的.

2 斑马鱼发育过程中糖链的多样性

最早的斑马鱼糖组学研究主要集中在个别酶的结构和功能上,基于MS技术对斑马鱼机体中糖复合物分析,发现其糖链具有多样性.Guerardel等[46]绘制了斑马鱼受精卵和早期胚胎( < 48 h post-fertilization,hpf)中主要糖蛋白和糖脂的糖链谱,分析表明斑马鱼胚胎中糖链结构具有多样性,在胚胎发育的各个时期均高丰度表达有唾液酸化糖链(末端为N-乙酰神经氨酸和N-羟乙酰神经氨酸)和高甘露型糖N-糖链(复杂型或寡聚)两类.在斑马鱼胚胎中唾液酸化程度很高,高甘露糖型N-糖链是唯一能检测到的非唾液酸化的糖链结构.复杂型N-糖链通常以Galβ1-4(Neu5Ac/Gc)Galβ1-4(Fucα1-3) GlcNAc这种独特的结构作为末端,黏蛋白型O-糖链通常以Fucα1-3GalNAcβ1-4(Neu5Ac/Neu5Gcα2-3) Galβ1-3GalNAc这种独特的结构作为末端(图 1).通过对大量特定的岩藻糖基化黏蛋白型O-糖链进行观察,发现这种聚糖上寡聚唾液酸化在胚胎发育的最初阶段( < 24 hpf)即可被观察到,而对于糖脂进行分析鉴定发现,多种寡聚唾液酸化的乳糖神经酰胺化合物只出现在在胚胎发育的后期阶段( > 24 hpf).这些研究表明,斑马鱼胚胎发育过程中蛋白质和脂质具有复杂多样的唾液酸化形式,为今后探索特异性唾液酸糖基转移酶活性和表达奠定了基础[47-51].Vanbeselaere等[52]通过将MS与NMR技术结合,发现在斑马鱼肝脏细胞系中糖链谱相对简单,糖蛋白糖链多为唾液酸化的多天线型N-糖链,此外还有一些含有斑马鱼特异性的糖链末端Galβ1-4(Neu5Ac/Gc)Galβ1-4(Fucα1-3) GlcNAc和核心1多聚唾液酸O-糖链.对这个细胞系中糖基转移酶进行表征发现,其糖链谱与已知的唾液酸和岩藻糖基转移酶的表达模式具有很好的相关性,此项研究为以后斑马鱼中糖基化的调控和糖链的功能研究提供了很有价值的参考依据.Takemoto等[53]对胚胎中岩藻糖基化的调控作用进行了表征,发现12 hpf复杂型糖链形成增多,同时岩藻糖基化糖链增多.Hase等[54]证明斑马鱼中两种α1, 3-岩藻糖基转移酶催化Lewis x的岩藻糖基化,这些酶在胚胎发生的不同时期受到严格调控,内源性糖苷酶水解糖蛋白产生了大量游离的寡聚糖,在其上发现Lewis抗原表位由岩藻糖基转移酶介导产生[55].

Fig. 1 The structures of abundant and unusual N-glycans and O-glycans isolated in zebrafish embryos 图 1 斑马鱼胚胎中特殊的糖链结构
3 糖基化在斑马鱼发育中作用的研究进展 3.1 斑马鱼突变体

特定蛋白质和脂质上的聚糖在斑马鱼发育中的功能研究可以通过吗啉代反义寡核苷酸类似物(Morpholino,MO)技术或建立糖链合成过程的糖基转移酶和核苷酸糖转运蛋白基因突变的鱼系(表 1)来进行[56].其中,slytherin(srn)突变体,使参与GDP-岩藻糖生物合成(GDP-mannose 4, 6-dehydratase或gmds)的限速酶产生错义突变,造成蛋白岩藻糖基化变化,从而引起神经形成和胶质细胞分化,轴突寻路和突触形成缺陷,形成异常的神经、肌肉和中枢神经系统[57-58].还有一些表型的产生是由于Notch通路的减弱,Notch通路中的受体均为N-和O-连接的岩藻糖基化聚糖,研究证明这些糖链的变化会改变下游信号的传递[59-62].在srn突变体产生的这些表型中,其中视网膜-视顶盖连通性受到影响与Notch通路不相关.通过对研究分析gmds另一个等位基因突变体towhead(twd),发现迷走运动神经祖细胞的迁移需要神经上皮细胞中表达岩藻糖基化聚糖进行调控[63],它也与Notch通路信号变化无关,可能影响到其他信号通路的活性,见下文.

Table 1 Known zebrafish glycosylation mutants 表 1 斑马鱼糖基化相关突变体
3.2 岩藻糖基转移酶

在很多生物化学和分子生物学的研究中涉及到末端岩藻糖残基,它在很多细胞进程中发挥很重要的作用[70].末端岩藻糖由岩藻糖基转移酶介导修饰糖脂或糖蛋白[70].多种癌症的发生都伴随着Fut8异常表达,而Fut8的产物核心岩藻糖N-糖链分布在多种糖蛋白中,它在信号通路中发挥重要作用.Fut8对于生长发育有重要作用,Subsequent等实验发现,Fut8基因敲除小鼠表现出明显的生长延迟和初生死亡率升高,证明了跨膜受体的核心岩藻糖基化对于其在细胞内的能量逐级传导是必需的,例如TGF-1、EGF和LRP-1、α3β整联蛋白的受体[71-75],缺乏核心岩藻糖基化会使这些受体与配体的结合力受到影响,从而使机体表型或机能异常.

在果蝇中,脂蛋白颗粒可以作为脂质修饰蛋白的运输工具促进信号通路,例如介导Shh信号通路的刺猬蛋白.Seth等[76]研究发现,敲降一个Fut8反应底物载脂蛋白B(ApoB)(主要负责脊椎动物脂蛋白颗粒的聚集和分泌的支架蛋白),会使斑马鱼发育中线模式受损,敲降Fut8在斑马鱼胚胎中也产生了相似的表型,也就是说,在斑马鱼发育中,ApoB核心岩藻糖基化程度降低会影响Shh信号通路活性从而使斑马鱼发育受到影响(表 2).Fut8 Mo会减少或打乱来自运动神经元和背根神经节轴突投射,与Shh通路突变体sonic you (syu),smoothened(smo)和detour(dtr)产生的表型相似[77-78].从smuyot突变体以及对Fut8 Mo的敏感性看出,Shh信号会延缓肌肉和固有、体节构架形成,Fut8 Mo和syusmu中神经嵴迁移紊乱,造成颌骨缺损[79-80].Shkumatava等[81]发现在Shh信号通路突变体和Fut8 Mo中,在视网膜发育中会产生视网膜神经节细胞、胶质细胞、光感受器数量剧烈减少的表型.在smu突变体和Fut8 Mo中,眼部细胞增殖加快,这些都是由于Shh信号通路是从细胞周期中退出所必需的,所有这些结果表明,核心岩藻糖基化对眼部的正常发育是必要的.

Table 2 Function of glycosyltransferase in zebrafish embryo development 表 2 斑马鱼胚胎发育过程中糖基转移酶的调节功能
3.3 甘露糖基转移酶

据目前所知,在哺乳动物的脑、神经和骨骼肌中发现有少量O-甘露糖基化糖蛋白[82-85],哺乳动物O-甘露糖残基通常扩展连接有唾液酸、岩藻糖等,其中Siaα2-3Galβ1-4GlcNAcβ1-2Manα1-Ser/Thr是α-抗肌萎缩蛋白糖链(α-dystroglycan,α-DG)与层黏连蛋白G结构域结合所必需的(图 2).大多肌营养不良都与肌萎缩蛋白的糖基化缺陷有关,进行性肌营养不良是由于抗萎缩肌蛋白编码突变引起造成的;先天性肌营养不良(CMDs)是由α-抗肌萎缩蛋白糖基化缺陷引起的.基因组研究证实了这种与营养不良相关的功能性糖基化基因对于功能性糖基化在斑马鱼中是保守的[86-87].抗肌萎缩蛋白形成α-抗肌萎缩蛋白糖蛋白复合物(DGC).各种肌营养不良的疾病包括沃克-沃伯格综合征(WWS)、肌肉眼脑疾病等都称之为α-抗肌萎缩蛋白糖基化病变.O-甘露糖基转移酶(POMT1POMT2)催化O-连接甘露糖链第一步反应,人类POMT1POMT2基因的缺陷会导致WWS发生,POMGnT将UDP-GlcNAc上的GlcNAc转运形成O-连接的甘露糖糖链.其他潜在的糖基转移酶可以对哺乳动物O-甘露糖基化的形成起促进作用[87-88].斑马鱼提供了一个研究人类肌肉疾病如肌营养不良的模型[89],一些研究者采用反向遗传技术来解释糖链在斑马鱼发育中的作用并建立了糖基化缺陷疾病研究模型.总之,O-甘露糖基化结构在脊椎动物中类似.因此,斑马鱼可以作为分析脊椎动物O-甘露糖基化生物合成、肌营养不良、肌形成的模型.

Fig. 2 The structure Siaα2-3Galβ1-4GlcNAcβ1-2Manα1-Ser/Thr is required for binding between α-dystroglycan(α-DG) and laminin G domain 图 2 Siaα2-3Galβ1-4GlcNAcβ1-2Manα1-Ser/Thr结构是α-DG与层黏连蛋白结合所需

与肌营养不良形成相关的因子有POMT1、POMT2、POMGnT1、抗肌萎缩蛋白、fukutin蛋白和fukutin相关蛋白(FKRP).在斑马鱼中敲减α-抗肌萎缩蛋白糖基化病变的基因FKRP,产生的表型与人类由FKRP突变引起的肌营养不良表型相似.FKRP MO与zPOMTs突变体胚胎中显示α-DG糖基化程度降低,层黏连蛋白结合降低,导致肌肉神经元和眼睛异常[90-91],说明FKRP会影响O-连接甘露糖链的生物合成. zPOMT1 Mo和zPOMT2 Mo,会致斑马鱼胚胎产生身体弯曲、心包水肿、眼部色素沉降[92](表 2),此外,zPOMT2 Mo使α-肌萎缩蛋白抗糖基化抗体(IIH6) 活性降低,说明肌营养不良蛋白的聚糖上O-甘露糖基化发生了改变[86].

3.4 O-GlcNAc转移酶

在许多哺乳动物细胞中,许多蛋白被GlcNAc残基修饰,它通过OGT催化合成,参与许多生物过程,如信号因子的磷酸化作用、细胞骨架构成、己糖生物途径等.OGT存在于细胞质和细胞核中.蛋白的O-GlcNAc在细胞传导营养物质、毒性应激、热力等方面有作用.在发育过程中几个关键蛋白都被O-GlcNAc修饰,例如NeuroD1、β-catenin、E-钙黏素以及其他一些蛋白如:CK-Ⅱ、RNA聚合酶Ⅱ、细胞核核心蛋白、转录因子等,O-GlcNAc与细胞转录、蛋白质结构稳定、细胞周期等有关.OGT可以对外部刺激迅速做出反应.与其他复杂的糖基化不同的是,就像磷酸化作用那样,O-GlcNAc糖基化是具有高度动态和瞬时变化性的.

Webster等[93]将OGT Mo或O-GlcNAc糖苷酶(OGA)过表达会导致斑马鱼胚胎体轴缩短、大脑体积缩小、细胞死亡率增加,同时也延迟卵外包以及造成卵黄合胞体层内细胞骨架破坏(表 2).酶的变化间接影响糖基化程度也在斑马鱼突变体中得到了表征,胚胎外卵黄合胞体层中细胞骨架肌动蛋白和微管蛋白严重地解体,这种细胞骨架的缺陷与之前报道的胚胎中Pou5f1/Oct4转录因子功能缺失所产生的表型类似,在人的胚胎干细胞中,Pou5f1/Oct4是由O-GlcNAc修饰的.

3.5 唾液酸转移酶

多聚唾液酸-神经细胞黏附分子是介导细胞间和细胞-基质间黏附的单链跨膜糖蛋白,它在中枢神经系统很多部位存在并发挥作用.St8Sia家族的酶将唾液酸转运至糖蛋白或糖脂上,神经元的迁移和斑马鱼大脑发育过程中脑部结构塑造与stx/St8sia2和pst/St8sia4这两种多聚唾液酸转移酶息息相关.通过酶消除法去除唾液酸化会对中脑和后脑发育中部分连合轴突寻路产生不良影响.Bentrop等对编码一个寡聚唾液酸化糖基转移酶St8Sia3基因进行研究,这个酶在神经系统的发育中表达较弱,但在体节及体节衍生结构中大量表达,利用Mo敲减St8Sia3基因,会造成体节肌肉形态异常,包括边界形成和肌腱连接完整性受到破坏,说明这个糖基转移酶在斑马鱼构架形成中具有重要作用[50-51, 94](表 2).

3.6 半乳糖基转移酶

β1, 4-半乳糖基转移酶(β4Galt1、β4Galt5) 在斑马鱼胚胎早期发育中参与半乳糖基化作用.β4Galt1 Mo会导致原肠胚形成时期异常的集中延伸运动,同样减弱β4galt5的表达会影响胚胎发育中背腹模式形成,蛋白聚糖上异常的半乳糖基化,会改变Bmp2依赖的信号通路[95](表 2).Vasta等[96]研究强调了半乳糖结合凝集素在斑马鱼胚胎形成中的重要作用,这一类凝集素调节胶质细胞分化、骨骼肌发育、感光杆细胞再生,因此那些特异性的末端半乳糖N-糖链对于半乳凝集素在发育中的功能具有重要作用.

另外,也有研究者通过对凝集素MPL(maclura pomifera)、PNA(peanut agglutinin)、WGA(wheat germ agglutin)进行标记,对斑马鱼从卵子到受精卵,再到胚胎发育中的神经形成等生物过程中,糖链的表达变化情况进行观察测定,并从中发现特定的发育阶段里特异表达的糖链结构[97-99].

4 糖胺聚糖(GAG)与斑马鱼

复合糖类在斑马鱼发育过程中的作用研究,多围绕GAGs合成和修饰上的缺陷造成的影响进行.目前知道的突变体会影响硫酸乙酰肝素(HS)、硫酸软骨素(CS)和透明质酸酸(HA)的合成[100].现有已知的突变体都会对GAGs造成影响,包括产生糖核苷酸前体(uxs1udgh/jek)[67, 69],负责GAG合成的糖基转移酶(ext2/dak、extl3 /box、xylt1)[64-66]以及参与硫酸化或磷酸化作用的蛋白(papst1/picC4ST-1fam20b)[65-66, 101],这些酶的缺失会造成颅面软骨形成、骨骼发育、心脏瓣膜的形成等缺陷(表 1).在一些情况下uxs1udgh/jekxylt1fam20bext2/dakpic,会改变GAGs的合成或修饰,从而影响颅面软骨形态形成和成熟,除此之外,成骨细胞标志物如runx2b和Osterix茜素红染色的变化说明这些突变体同样还会影响软骨形成、骨的形成.在uxs1dakpic突变体中,GAG表达减少导致成骨过程减慢.相反地,在xytl1fam20b突变体中,软骨细胞成熟,造骨细胞分化以及骨的形成速度加快[66].GAG的合成减少对心脏瓣膜的形成也有不利影响.在udgh突变体jek(CS、HS和HA产物缺陷),心房细胞和心室腔室边缘的细胞不能够被很好地区分出来,并因此心内膜垫和瓣膜形成失败.同样,Peal等[100]证明化学或遗传抑制CS生物合成也扰乱了此过程,证明斑马鱼的卵囊、心胶质以及房室瓣膜形成中都富含CS,它的衰竭将损害瓣膜细胞的迁移和垫层形成.当细胞分泌大量细胞外基质(ECM)往往会出现GAG依赖型胚胎缺陷.在一些突变体中,异常表型的产生与生长因子信号通路的改变有关,特别是ext2/dak表达减弱后通过测定Fgf和Wnt通路的下游目标分子的表达,发现信号通路活性减弱[102].Yost等[103]研究发现降低HS的硫酸盐化作用会减弱Wnt信号通路活性以及依赖于Wnt信号通路形成的外包,再次将通路中关键分子β-catenin激活,会减弱这种不良影响.

5 总结与展望

越来越多的研究表明,在斑马鱼的发育过程中,其神经系统、肌肉组织、器官等的形成均受到糖基化作用的调控.对于糖链在胚胎形成过程中的功能研究也将深入下去,将糖组学应用于基于斑马鱼为模式生物的研究也会更加普遍广泛,为目前现有的研究技术,如构建突变体、正反转基因技术、Mo的应用等提供新的角度和思路.然而对于糖基化在斑马鱼再生过程中发挥的作用的研究还几乎没有涉及,但已经有以小鼠为模式生物来探索糖链在组织器官再生中功能的研究,并且证明了糖基化在此过程中具有重要的调节作用.Wang等[104]通过使用70%部分肝切除的小鼠模型深入研究了Fu8在肝脏再生中的作用,Fut8的活性在切除后前4天升高,而在后面时间趋于正常水平.缺少Fut8会抑制肝细胞增殖从而延缓肝脏的再生过程,Fut8敲除小鼠肝脏中EGFR等糖蛋白的岩藻糖基化水平降低,从而造成这些受体对胞外配体的应答能力也相应减弱,通过额外诱导Fut8表达,可以增加这些蛋白的岩藻糖基化程度,促进下游信号通路的活性及相关基因的转录调控,进而促进肝脏细胞增殖及肝脏再生(图 3).Sano等[105-106]发现存在于细胞外基质和血浆中的多功能糖蛋白纤连蛋白(FN)和玻连蛋白(VN)糖基化变化参与小鼠肝脏再生调控,采用LC/MSn技术,在部分肝脏切除后FN中鉴定到8种复杂类型N-糖链结构,其中以双天线和三天线型为主要结构,手术组中FN和VN岩藻糖基化显著上升,唾液酸化降低.小鼠肝星状细胞VN的去唾液酸化降低了细胞的活性,也就是说在局部肝脏切除术后VN的活性的降低主要是由唾液酸化程度降低而引起.术后24 h,对肝脏进行局部切除,肝脏再生的早期阶段中就已经合成VN,N-连接的岩藻糖基化升高,而唾液酸化程度显著降低.在肝脏再生过程中,术后VN糖基化的变化可调节的肝星状细胞生存、激活和增殖,因为VN作为反应底物,它的黏附和分布是细胞增殖和活性的先决条件.这些蛋白糖基化的改变影响了细胞在再生过程中的增殖、识别、黏附.研究已经证明斑马鱼的心脏、尾鳍、视网膜等器官均具有很强的再生能力,在它们再生过程中,多种信号通路参与不同阶段的调控,其中绝大多数信号分子都是糖蛋白,我们可以大胆地假设,这些信号蛋白的糖基化必定在细胞的增殖、去分化、再分化等过程中具有举足轻重的作用.成年哺乳动物不具备断肢或损伤心肌组织的再生能力,受损的脑组织和脊柱也不能恢复,研究斑马鱼组织器官的再生机制,为我们今后在再生医学方面提供了研究基础,可通过Mo、CRISPR/CAS9、TALEN(transcription activator-like effector nucleas)等基因编辑技术、活体成像技术、细胞追踪技术以及其他糖组学技术探索不同的糖基化在再生调控过程中发挥的作用,对斑马鱼的发育及再生机制有更深层次的了解,为人类肢体再生或其他组织器官的再生提供有价值的信息.

Fig. 3 Proposed molecular mechanisms for the delayed liver regeneration in Fut8-/- mice 图 3 Fut8-/-小鼠肝脏再生分子机制
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中国科学院生物物理研究所和中国生物物理学会共同主办
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文章信息

贾丽苑, 冯娟涛, 崔继红
JIA Li-Yuan, FENG Juan-Tao, CUI Ji-Hong
糖基化对斑马鱼发育及再生作用的研究进展
Glycosylation Related to The Development and Regeneration of Zebrafish
生物化学与生物物理进展, 2017, 44(10): 908-918
Progress in Biochemistry and Biophysics, 2017, 44(10): 908-918
http://dx.doi.org/10.16476/j.pibb.2017.0365

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收稿日期: 2017-09-18
接受日期: 2017-09-26

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