,1,2, 李庆伟,1,2Lamprey: an important animal model of evolution and disease research
Yigao Zhu1,2, Jun Li1,2, Yue Pang,1,2, Qingwei Li,1,2通讯作者: 逄越，博士，教授，研究方向：分子免疫进化。E-mail:pangyue01@163.com;李庆伟，博士，教授，研究方向：细胞遗传学。E-mail:liqw@263.net
责任编辑: 于黎
收稿日期:2020-02-20修回日期:2020-06-28网络出版日期:2020-09-20
| 基金资助: |
Received:2020-02-20Revised:2020-06-28Online:2020-09-20
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作者简介 About authors
朱医高,在读硕士研究生,专业方向：微生物学。E-mail:
李军,博士,研究员,研究方向：细胞遗传学。E-mail:
摘要
七鳃鳗是现存的无颌类脊椎动物代表之一,距今已有5亿多年的历史,素有“活化石”之称。古老的七鳃鳗凭借独特的功能特征和进化地位吸引了众多****的注意：在免疫系统方面,七鳃鳗具有不同于有颌类脊椎动物的适应性免疫系统和免疫分子;基于进化地位,七鳃鳗作为一种重要的发育进化模式动物可以解析脊椎动物进化保守性和衍生的特点,七鳃鳗大脑皮层为哺乳动物大脑皮层的进化提供蓝图; 在疾病研究中,七鳃鳗作为脊髓损伤功能再生和胆道闭锁病理模型取得了阶段性成果。本文结合国内外相关报道,详细介绍了七鳃鳗的免疫分子、发育进化以及生理结构的研究进展,以期为深入开展七鳃鳗在动物遗传发育和生物医学领域的研究产生积极地推动作用。
关键词：
Abstract
Lamprey is one representative of the extant jawless vertebrates, known as “living fossils”, with a history of more than 500 million years. The ancient lamprey has attracted the attention of many scholars due to its unique functional characteristics and evolutionary status. In terms of immune system, the lamprey has adaptive immune system and immune molecules different from those of jawed vertebrates. Based on the evolutionary status, lamprey is an important developmental and evolutionary animal model for analyses of evolutionary conservation and derivative characteristics of vertebrates. Lamprey pallium provides an evolutionary blueprint for mammalian cerebral cortex. In disease research, lamprey has provided various results as a pathological model of spinal cord injury and biliary atresia. In this review, the life cycle, immune molecules, developmental evolution and physiological structure of lamprey are presented in details in reference with relevant reports from China and abroad. We believe that in-depth studies of lamprey could promote an effective outcome(s) in the research on genetics of animal development and biomedicine.
Keywords：
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朱医高, 李军, 逄越, 李庆伟. 七鳃鳗：生物进化和疾病研究的重要模式动物. 遗传[J], 2020, 42(9): 847-857 doi:10.16288/j.yczz.20-045
Yigao Zhu.
七鳃鳗(lamprey)又称八目鳗、七星子,是现存的无颌类脊椎动物之一[1],按照动物分类学隶属于脊椎动物亚门、圆口纲、七鳃鳗目、七鳃鳗科,该属动物全世界共有10属44种[2]。其中有8属分布于北半球,包括七鳃鳗属(Lampetra)、海七鳃鳗属(Petromyzon)、里海七鳃鳗属(Caspiomyzon)、鱼吸鳗属(Ichthyomyzon)、叉牙七鳃鳗属(Lethenteron)、双齿七鳃鳗属(Eudontomyzon)、楔齿七鳃鳗属(Entosphenus)和四齿七鳃鳗属(Tetrapleurodon);南半球仅存2属,囊口七鳃鳗属(Geotria)与袋七鳃鳗属(Mordacia)[3]。在我国有3种七鳃鳗：日本七鳃鳗(Lampetra japonica) (图1A)、东北七鳃鳗(Lampetra morii) (图1B)和雷氏七鳃鳗(Lethenteron reissneri) (图1C)。日本七鳃鳗体型较大,主要分布于黑龙江水系;雷氏七鳃鳗体型较小,分布于黑龙江、松花江及嫩江;东北七鳃鳗体型介于雷氏七鳃鳗和日本七鳃鳗之间,分布于我国辽河流域、鸭绿江等地区。七鳃鳗头部前端有一个圆形漏斗状的口漏斗(buccal funnel) (图1,a~c),内面有表皮形成的角质齿,这些角质齿齿式是七鳃鳗分类的重要形态学特征。
图1
新窗口打开|下载原图ZIP|生成PPT图1中国3种七鳃鳗
A：日本七鳃鳗;B：东北七鳃鳗;C：雷氏七鳃鳗。a：日本七鳃鳗口漏斗;b：东北七鳃鳗口漏斗;c：雷氏七鳃鳗口漏斗。比例尺为1 cm。
Fig. 1The characteristics of three types of lampreys in China
七鳃鳗生命周期分为3个阶段：幼体、变态期和成体。幼体七鳃鳗目盲、无齿,主要通过滤食浮游生物为食,在淡水中生长4~6年后迁徙到海洋中,经历变态发育过程出现了具有真正视觉功能的眼睛、吸盘逐渐形成、体长增加、背鳍增大[4]。此外,变态期间七鳃鳗体内器官发生了重要变化——胆管逐渐消失[5],这一变化使七鳃鳗成为唯一的在发育过程中胆管能够自发消失的脊椎动物。变态期的七鳃鳗在海洋中生长2~3年发育为成体七鳃鳗,此后七鳃鳗通过吸盘吸附于鱼体吸食血肉而生存。因此七鳃鳗是一种半寄生生物(并非所有的七鳃鳗都是半寄生生物,有23~26种七鳃鳗终生非寄生性生存)。为了适应不同区域的水域环境,七鳃鳗体内形成了一个渗透调节策略,无论处于淡水还是海水中其血液Cl-离子浓度都能够保持相对平衡[6]。七鳃鳗在整个生命周期中只产一次卵,性成熟后会迁徙到淡水区域产卵,产卵后在2~3周内死亡[7]。七鳃鳗的繁殖与其发达的嗅觉系统密不可分,研究发现在海洋中雄性七鳃鳗产生的精胺能够吸引性成熟的雌性七鳃鳗与其交配[8]。生活在溪流中的幼体七鳃鳗能够释放出微量的多组分甾族信息素吸引成体七鳃鳗到此处产卵,已有研究证实极低浓度(低于1 pmoL/L)的该化合物就能够吸引成体七鳃鳗[9],这一生物学特征为研究化学物质介导信号传递提供了很好的研究模型。七鳃鳗独特的生活方式、形态、功能及生理结构特点逐渐引起科学家的研究兴趣。早期研究主要涉及比较解剖学和脊椎动物的进化研究,七鳃鳗具有许多脊椎动物最原始的特征如神经嵴、基板、分节的脑、成对的感觉器官和咽,研究其结构和发育机制有助于了解脊椎动物的原始特征及进化历程[10]。
最近10年国内外关于七鳃鳗的研究报道显著增多[11,12,13,14,15,16,17,18,19,20],这与七鳃鳗具有独特的适应性免疫分子和独特的功能相关。研究表明,七鳃鳗适应性免疫系统不同于有颌类脊椎动物,七鳃鳗不含有T细胞受体(T cell receptors, TCRs)、B细胞受体(B cell receptors, BCRs) 和主要组织相容性复合体(major histocompatibility complex,MHC)介导的适应性免疫系统,而是基于免疫分子——可变淋巴受体(variable lymphocyte receptors, VLRs)为基础形成的适应性免疫系统识别抗原[21],七鳃鳗免疫系统揭示了脊椎动物免疫系统的原始特征。从进化角度,七鳃鳗是研究脊椎动物进化重要模式动物。Fain[22]最新研究指出七鳃鳗视网膜感光器的许多信号转导机制与其他脊椎动物的信号转导机制极为相似,表明脊椎动物将光信号转化为电信号的基本机制在古老的七鳃鳗中就已经存在,而与七鳃鳗亲缘关系最近的盲鳗(hagfish)不具有真正意义的视觉系统,其眼睛已退化,因此七鳃鳗视觉系统的研究对揭示脊椎动物视觉功能进化具有重要意义。此外,由于七鳃鳗基因组含有高度重复序列且富含鸟嘌呤和胞嘧啶,对后期基因组装带来较大的挑战。近年来,随着测序技术的发展,已获得了七鳃鳗全基因组数据[23],促进了对七鳃鳗的深入解析,传统生物学无法解释的现象借助基因组学能够得到很好的阐明[24]。在疾病模型研
究领域,七鳃鳗在脊髓损伤后表现出强大的再生修复能力,短期内能够恢复正常运动,因此作为脊髓损伤模型被广泛研究[25];此外,七鳃鳗在生长发育中胆管会自发消失能够模拟新生儿胆道闭锁症状[26]。鉴于七鳃鳗的重要地位及作用,本文主要从独特的免疫分子、生物进化以及在疾病模型研究等方面对七鳃鳗进行了详细介绍,希望以此为契机推动我国七鳃鳗研究的发展。
1 七鳃鳗拥有独特的免疫分子
1.1 适应性免疫系统的哨兵——可变淋巴受体
七鳃鳗作为最原始的脊椎动物不具有胸腺、脾脏和骨髓等免疫器官,缺失有颌类脊椎动物适应性免疫系统的重要组成成分——TCRs、BCRs和MHC分子。七鳃鳗肠沟、前肾和神经轴体组织中存在大量的类淋巴细胞[27],病原菌感染七鳃鳗后能够产生强烈的免疫应答反应[28,29],研究发现识别病原菌入侵的分子是VLRs[21,30]。成熟的VLRs 基本结构是由胚系vlrs基因随机插入富含亮氨酸的重复序列(leucine- rich repeats, LRRs)而形成,通过LRRs模块的插入能够使七鳃鳗胚系基因形成超过1014种VLRs,其多样性足以应对外界多变的抗原[31]。成熟vlrs基因组装是通过胞嘧啶脱氨酶1和2调控基因转换机制完成,该过程不同于有颌类脊椎动物免疫球蛋白(immunoglobulins, Ig)通过Variable(V)、Diverse(D)和Joining(J)基因片段重排介导的高度多样性Ig和TCRs的产生[32,33,34]。VLRs包括3种形式,即VLRA、VLRB和VLRC。VLRA和VLRC以跨膜蛋白的形式存在于细胞表面,主要在七鳃鳗咽和肠道上皮细胞中表达[28];VLRB属于分泌型蛋白质,主要分布在七鳃鳗造血组织和肾脏区域[35]。分泌型VLRB是由4~5个二聚体通过二硫键连接而成的五聚体,它们分别具有8~10个抗原结合位点,在形态学上与高等哺乳动物IgM存在高度相似性[36]。有报道证实在七鳃鳗中表达VLRA+和VLRB+类淋巴细胞分别等同于有颌类脊椎动物的T淋巴和B淋巴细胞[37]。七鳃鳗VLRs能够产生与哺乳动物免疫系统相匹敌的免疫受体多样性,这一特征奠定了七鳃鳗在脊椎动物适应性免疫起源及进化中的重要地位[38,39]。此外,由于七鳃鳗与其他哺乳动物亲缘关系较远,VLRs能够突破因哺乳动物免疫耐受而不能产生Ig的限制,可以识别更广泛的抗原表位。因此,对VLRs功能的研究在免疫性疾病的治疗上具有广阔的应用前景。
1.2 抗肿瘤活性的免疫蛋白
固有免疫在抵御外来病原体入侵中发挥重要的作用,其可以维持宿主免疫反应和保护感染组织间的平衡,该过程必须被精细识别与调控。研究表明,固有免疫识别及调控主要通过一系列胚系编码的模式识别受体(pattern recognition receptor, PRR)来识别病原微生物表达的保守的病原体相关分子模式(pathogen associated molecular pattern, PAMP),然后再清除病原体[40,41]。本课题组首次报道七鳃鳗血清对病原菌具有特异性的杀伤作用,并证实这一杀伤过程需要VLR、C3和C1q的参与[42];随后,本课题组又相继报道了七鳃鳗血清及神经轴体细胞分泌液具有杀伤肿瘤细胞的作用[43,44],并且通过吸附层析及阴离子交换层析等蛋白纯化方法并结合质谱分析从七鳃鳗神经轴体组织的分泌液中分离鉴定一种新型免疫蛋白,命名为七鳃鳗免疫蛋白(lamprey immune protein, LIP),重组LIP蛋白不但能够特异性识别肿瘤细胞而且对其具有强烈的杀伤作用,而同等剂量下对正常细胞没有作用[45]。HeLa细胞中过表达lip基因引起肿瘤细胞释放乳酸脱氢酶、活性氧爆发、激发p53信号通路并能够破坏内质网结构[46];进一步研究发现LIP蛋白与肿瘤细胞的结合靶点位于细胞膜的脂筏中,与N-羟乙酰神经氨酸(Neu5Gc)的N-糖链存在相互作用;晶体结构解析表明LIP蛋白质在N端含有Jacalin-like凝集素结构域,C端含有气单胞菌溶素结构域[47]。此外,基因组数据显示lip基因在七鳃鳗中表达丰富并且高度同源序列多达数十条。这些结果表明LIP蛋白是一种重要的免疫蛋白,在七鳃鳗免疫系统中发挥重要作用。七鳃鳗依赖LIP蛋白识别并杀伤外来病原体的途径不同于高等脊椎动物固有免疫防御机制,该途径为进一步探索LIP蛋白在无颌类脊椎动物固有免疫防御中的作用机制提供了新的线索。2 七鳃鳗在动物进化研究领域的重要地位
2.1 七鳃鳗基因组是研究分子进化的宝库
七鳃鳗基因组为研究脊椎动物的起源和现存生物基因组的进化事件提供了重要的资源。2013年科学家首次对海七鳃鳗进行了全基因组测序[23],这一里程碑事件对揭示七鳃鳗基因组学和动物基因进化具有重要意义。研究发现,七鳃鳗在胚胎发育中经历了大规模的程序化基因组重排和体细胞基因丢失,基因丢失作为永久性沉默机制阻止了特殊的基因在体细胞中表达[48,49]。2017年,海七鳃鳗生殖细胞基因组测序完成,该项研究为丢失基因的进化及其功能研究奠定了基础[50]。七鳃鳗的基因组数据表明其拥有诸多不同于其他脊椎动物和无脊椎动物的基因特征,这表明七鳃鳗的该部分特征是独立进化形成的。大多数脊椎动物的血红蛋白为四聚体,而七鳃鳗只存在单链血红蛋白[51]。同样,生化研究表明七鳃鳗的凝血机制比高等脊椎动物简单且仅存在外源性凝血系统[52]。通过分析七鳃鳗全基因组数据,发现其缺少编码凝血因子VIII和IX的基因,这两个基因对高等脊椎动物的内源性凝血系统至关重要[53];研究还发现七鳃鳗存在两个凝血因子X和3个凝血因子VII[54],这些结果表明在低等脊椎动物七鳃鳗中还没有进化出执行内源性凝血功能的基因,在动物进化中这些相关基因最开始出现于较为高等的有颌类脊椎动物中。另外,在有颌类脊椎动物中成对附肢(鱼的胸鳍和腹鳍,四足动物的前肢和后肢)的出现是一个重大的进化事件,因为它们的出现可以做更多形式的运动和完成更复杂的行为。七鳃鳗存在背鳍和尾鳍,但缺少成对的偶鳍,在鳍和附肢的发育过程中shh (sonic hedgehog)基因的表达必不可少[55,56,57];已有研究证明肢体特异性表达shh基因是由一个远程顺式增强子调控,通过对七鳃鳗基因组数据进行分析,没有检测到shh基因特异性调节元件,表明该调节元件是在有颌类脊椎动物中形成的,同时表明七鳃鳗可能具有不同的调控方式。七鳃鳗基因组对研究基因的进化具有极为重要的作用,本课题组借助雷氏七鳃鳗基因组数据库鉴定了7个肿瘤坏死因子受体(tumour necrosis factor receptors, TNFRs)成员,研究表明TNFRs成员的功能结构域在七鳃鳗中已基本形成并且在脊椎动物进化过程中高度保守,部分死亡受体成员TNFR10B、11B和21死亡结构域最早形成于硬骨鱼类[58]。由此可见,利用七鳃鳗基因组数据为研究物种进化的遗传基础提供了新思路,同时也说明七鳃鳗作为模式动物对研究脊椎动物基因的起源与进化关系具有重要作用。2.2 七鳃鳗可作为哺乳动物大脑皮层进化研究的模型
七鳃鳗是脊椎动物比较进化研究的模型[59],其已具有脊椎动物脑的基本结构,包含端脑(大脑)、间脑、中脑、小脑和延脑5部分。脊椎动物端脑表面覆有一层灰质称为大脑皮层,主要由神经元的胞体构成。早期研究将七鳃鳗大脑皮层分为外侧大脑皮层和由丘脑和神经元的纤维束组成的内侧大脑皮层[60]。哺乳动物大脑皮层主要由新皮层和古皮层(仅占10%)组成[61],前者由外向内依次为分子层、外颗粒层、外锥体细胞层、内颗粒层、内锥体细胞层和多形细胞层[62]。新皮层按照功能被划分为不同的感觉区域,包括运动区、视觉区和躯体感觉区[63]。哺乳动物的脑前额叶包含可引起眼睛和身体不同部位运动的区域,该区域的运动功能主要与大脑皮层的传出连接功能相关[64]。七鳃鳗大脑皮层投射神经元靶向脑干运动中枢和基底神经节亚核,具有明显的树突并延伸至外分子层从而具有像哺乳类和鸟类投射神经元锥体状特征。对七鳃鳗外侧大脑皮层的中心至末端部分进行微刺激能够引起眼、躯干、口腔运动,表明七鳃鳗大脑皮层和哺乳动物大脑皮层在传出功能连接和运动行为控制方面有明显的相似性[65],脊椎动物大脑皮层基本投射模式已经在古老的七鳃鳗大脑皮层中形成且在进化过程中未发生明显变化。在此基础上,Suryanarayana等[63]对七鳃鳗大脑皮层视觉区和躯体感觉区进行了功能探究,在七鳃鳗视网膜不同位置进行电刺激引起视网膜皮层映射,证实七鳃鳗外侧大脑皮层中存在一个明显的视觉区域,七鳃鳗形成的视觉通路与哺乳动物的外侧膝状体传递到主要视觉区域相类似;同时该研究指出七鳃鳗感觉信息是通过感觉三叉神经核和背柱核通过丘索通路传递到丘脑和大脑皮层,类似于哺乳动物。这些结果表明七鳃鳗大脑皮层在运动控制、躯体感觉和视觉方面已经进化出与哺乳动物相似的区域。2017年Suryanarayana等[66]对七鳃鳗外侧大脑皮层的结构进一步研究,明确指出七鳃鳗外侧大脑皮层存在具有1个分子层和2个内部细胞层的3层结构,最内层含有高密度的伽马氨基丁酸能(γ-aminobutyric acid-ergic, GABAergic)[67]和几乎等量的谷氨酸能细胞,外侧细胞层含谷氨酸能细胞数量更多,与爬行动物相似[68];整体统计,七鳃鳗大脑皮层有22%的细胞属于GABAergic细胞,该比例接近哺乳动物大脑皮层GABAergic细胞[69]。综上所述,七鳃鳗可作为哺乳动物大脑皮层进化研究的模型。
3 七鳃鳗在病理模型及疾病研究中的重要作用
3.1 在脊髓损伤功能再生研究领域的作用
脊髓属于中枢神经系统的一部分,在生物体内发挥关键作用,其与周围神经相连能够将来自上游神经系统中的信息传递至肌肉和器官从而完成各种生命活动[70]。高等哺乳动物脊髓损伤(spinal cord injury, SCI)能够造成SCI位点以下感觉和自主神经功能永久性的丧失,导致运动和感觉功能障碍,由于中枢神经系统的再生能力较低,这种损伤是不可逆转的[71]。与高等哺乳动物不同的是,七鳃鳗在脊髓完全横断8周后其功能会自行恢复并能正常的运动,这是由于七鳃鳗在SCI后大约50%的网状脊髓轴突会再生,同时脊髓回路及功能会得到重组和恢复[25]。研究发现七鳃鳗SCI后在网状脊髓神经元轴突周围积聚了大量伽马氨基丁酸(γ-aminobutyric acid,GABA),GABA的积累与相应神经元的高生存能力之间存在显著的相关性,推测GABA在七鳃鳗SCI后可能具有神经保护或促再生因子的作用[72]。此外,对功能恢复过程中的七鳃鳗脊髓和大脑进行RNA测序,发现轴突导向基因、细胞外基质相关基因以及增殖相关基因随着损伤后时间不同呈现差异表达,大约有3%的基因属于Wnt信号通路,表明Wnt信号通路在七鳃鳗脊髓功能恢复过程中发挥关键作用,阻断Wnt信号通路后抑制了七鳃鳗功能恢复[73]。Romaus-Sanjurjo等[74]指出内源性GABA可以促进七鳃鳗SCI后下行神经元的存活和轴突再生,使用GABA和巴氯芬(GABA-β受体激动剂)处理可以抑制七鳃鳗网状脊髓神经元caspase的激活并促进轴突再生;此外,经反义寡核苷酸处理,内源性GABA通过激活七鳃鳗SCI后下行神经元中表达的GABA-β受体,起到促再生因子的作用[74]。牛磺酸作为一种含硫的非蛋白质氨基酸在脑组织中发挥重要的功能,对脑部创伤有修复作用。最近一项研究在探究牛磺酸调节七鳃鳗SCI后轴突再生的作用时,发现使用牛磺酸处理能够促进七鳃鳗轴突的再生[75],该研究为哺乳动物神经系统损伤后促进轴突再生提供了一种新的方法,利用七鳃鳗作为脊髓损伤功能再生研究模型可为脊髓损伤患者新疗法的开发提供借鉴。
3.2 在胆道闭锁疾病领域中的作用
七鳃鳗是研究胆道闭锁疾病的最佳模式生物。胆道闭锁是一种伴有炎症、硬化性的婴幼儿胆管疾病,该病持续发展能够引起肝内外胆管出现阻塞导致胆汁淤积最终发生肝功能衰竭,是小儿外科领域中最重要的消化外科疾病之一,在出生婴儿中发病率达到1∶8000~1∶14000,亚洲报道的病例最多。目前最有效的治疗方法是早期进行肝移植手术。七鳃鳗在从幼体向寄生生活的成体变态发育过程中能够自发的逐步失去整个胆道系统,首先肝外胆管和胆囊先退化掉,然后肝内胆管逐渐消失[76],这种生理现象可类比人类胆道闭锁疾病[26]。最新证据表明转化生长因子β (transforming growth factor β, TGF-β)、Hedgehog、丝裂原激活蛋白激酶和Wnt信号通路参与了七鳃鳗胆管和胆囊退化,实验证明抑制TGF-β信号通路能够延缓胆管和胆囊退化[77]。七鳃鳗作为研究胆道闭锁的动物模型具有其他模式动物无法取代的优势。在小鼠(Mus musculus)中通过结扎或者切除胆管来建造胆道闭锁模型不能很好的反映人类胆道闭锁症状,另外对动物的选择以及实验操作要求较高,最终的结果并不理想。七鳃鳗的肝脏与哺乳动物的肝脏具有相似的组织学结构和超微结构[78],七鳃鳗无需通过注射药物或者经过特殊处理来建造模型,在发育过程中能够自发形成胆道闭锁症状。研究表明,七鳃鳗在变态发育的起始肝细胞中伴有炎症发生,细胞外间隙以及在胆管周围能够检测到大量的纤维化和坏死细胞,同时伴随着巨噬细胞增加以清除纤维化和坏死的细胞碎片[79]。在人类的胆道疾病中也观察到胆管损伤与巨噬细胞存在着相关性。有研究指出患有原发性硬化性胆管炎患者的肝脏中能够持续性激活巨噬细胞,导致释放TGF-γ,引起炎症和肝组织纤维化[80]。七鳃鳗能够通过特殊的信号机制来清除纤维化,若能够通过七鳃鳗模型确定激活巨噬细胞清除纤维化而不是诱导巨噬细胞产生慢性炎症和纤维化的细胞因子,将有助于治疗人类胆道闭锁及相关肝脏疾病。
3.3 在治疗人类肥胖疾病方面的作用
哺乳动物体内的脂肪组织分为白色脂肪组织和棕色脂肪组织,前者主要由成熟的白色脂肪细胞组成,包含单个大的脂滴和一个居于细胞边缘的细胞核,能够以甘油三酯的形式储存多余的能量,在高能量需求时甘油三酯转化为游离脂肪酸释放到血液系统中供使用[81];棕色脂肪组织在形态上不同于白色脂肪组织,包含多个微小的脂滴和一个位于中央的细胞核以及大量的线粒体[82]。与白色脂肪组织不同,棕色脂肪组织是体内产生热量的主要器官,也是一个内分泌器官,分泌信号因子,激活脂肪和碳水化合物的代谢,此过程主要依赖于解偶联蛋白1 (uncoupling protein-1, UCP1)的活性。UCP1是位于棕色脂肪细胞线粒体内膜的一种跨膜蛋白,在棕色脂肪组织中高表达且是棕色脂肪细胞的标记分子,能够允许质子重复进入线粒体从而消除驱动ATP合成的电化学梯度,最终以热的形式释放出大量的化学能[83]。最近的研究发现,在雄性成体海七鳃鳗的背鳍前缘脂肪组织能够产生大量的热量、富含不饱和脂肪酸、含有多腔的脂肪细胞并富含线粒体;转录组数据表明该区域基因同七鳃鳗鳃组织和肌肉组织相比较参与脂肪细胞分化的基因上调而参与氧化磷酸化偶联ATP合成的基因下调,众多迹象表明该区域存在棕色脂肪细胞[84]。此外,本课题组在日本七鳃鳗脑中也发现了棕色脂肪细胞的存在并通过基因克隆技术克隆出日本七鳃鳗ucp1、ucp2和ucp4基因。棕色脂肪细胞能够快速氧化自身储存的脂肪产生热量、增加代谢率[85]。研究表明棕色脂肪组织的活性与人类肥胖存在负相关性[86,87],瘦人(健康者)体内的棕色脂肪组织含量及其活性是肥胖者的四倍[88],同时肥胖者更容易产生并发症如II型糖尿病、心血管疾病[89]。目前棕色脂肪组织的适应性产热机制已经成为研究肥胖疾病的焦点[90]。结合七鳃鳗棕色脂肪组织的分布和特点,七鳃鳗为进一步研究和应用棕色脂肪在人类减肥及其并发症的治疗方面有着很好的参考意义。4 结语与展望
七鳃鳗作为最古老的脊椎动物迄今已有5亿多年的历史[91],在漫长的进化历程中与其同时期的物种绝大多数都已灭绝,而现存的七鳃鳗作为“活化石”记载着脊椎动物起源的整个过程,从溯源研究人类和其他高等哺乳动物的遗传和进化方面,七鳃鳗有着不可替代的作用。这种不可替代性主要表现以下几个方面：(1)基因组保持脊椎动物最原始的特点,对研究起源和进化有着独一无二的作用;(2)在生理结构方面,七鳃鳗适应环境的特点至今没有揭晓,这些特征的研究对于人类防御病原体的侵入有着另辟蹊径的启示;(3)新的基因和未知蛋白的重要生理功能为该研究领域蒙上一层神秘的面纱,这些重要功能的蛋白是人类新药开发的宝库。此外,七鳃鳗在疾病模型研究中有明显的优势,成体七鳃鳗胆管消失但是它们如何清除掉体内的胆盐并且不会发生肝硬化或者肝功能衰竭,这一独特的机制希望在不久的将来能够得到精确解析,为人类胆道闭锁及其相关的肝脏疾病的治疗提供借鉴;七鳃鳗具有强大的功能再生能力,脊髓横断后在短期内能够恢复正常的运动,这种罕见的功能特点对治疗脊髓损伤的病人具有重要的参考价值;根据LIP蛋白对肿瘤细胞的特异性识别和杀伤特点可作为人类癌症的诊断分子及靶向治疗癌症的药物。七鳃鳗作为地球上最古老和神秘的生物之一,值得更多的****去探索其奥秘。最近,本课题组完成了世界首个雷氏七鳃鳗基因定位于染色体水平的基因组测序,为进一步推动七鳃鳗的分子生物学研究起到积极的作用,同时也期待与国内外的同行携手将七鳃鳗的研究全方位地深入开展,更好地造福于人类的生命健康事业。参考文献 原文顺序
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被引期刊影响因子
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DOI:10.1152/ajpregu.00033.2019URLPMID:31747320 [本文引用: 1]
Lampreys are the most basal vertebrates with an osmoregulatory strategy. Previous research has established that the salinity tolerance of sea lamprey increases dramatically during metamorphosis, but underlying changes in the gut have not been examined. In the present work, we examined changes in intestinal function during metamorphosis and seawater exposure of sea lamprey (Petromyzon marinus). Fully metamorphosed juvenile sea lamprey had 100% survival after direct exposure to 35 parts per thousand seawater (SW) and only slight elevations in plasma chloride (Cl(-)) levels. Drinking rates of sea lamprey juveniles in seawater were 26-fold higher than juveniles in freshwater (FW). Na(+)-K(+)-ATPase (NKA) activity in the anterior and posterior intestine increased 12- and 3-fold, respectively, during metamorphosis, whereas esophageal NKA activity was lower than in the intestine and did not change with development. Acclimation to SW significantly enhanced NKA activity in the posterior intestine but did not significantly change NKA activity in the anterior intestine, which remained higher than that in the posterior intestine. Intestinal Cl(-) and water uptake, which were observed in ex vivo preparations of anterior and posterior intestine under both symmetric and asymmetric conditions, were higher in juveniles than in larvae and were similar in magnitude of those of teleost fish. Inhibition of NKA by ouabain in ex vivo preparations inhibited intestinal water absorption by 64%. Our results indicate drinking and intestinal ion and water absorption are important to osmoregulation in SW and that preparatory increases in intestinal NKA activity are important to the development of salinity tolerance that occurs during sea lamprey metamorphosis.
DOI:10.1007/s10499-017-0190-6URL [本文引用: 1]
DOI:10.1371/journal.pbio.3000332URLPMID:31287811 [本文引用: 1]
Semen is fundamental for sexual reproduction. The non-sperm part of ejaculated semen, or seminal plasma, facilitates the delivery of sperm to the eggs. The seminal plasma of some species with internal fertilization contains anti-aphrodisiac molecules that deter promiscuity in post-copulatory females, conferring fitness benefits to the ejaculating male. By contrast, in some taxa with external fertilization such as fish, exposure to semen promotes spawning behaviors. However, no specific compounds in semen have been identified as aphrodisiac pheromones. We sought to identify a pheromone from the milt (fish semen) of sea lamprey (Petromyzon marinus), a jawless fish that spawns in lek-like aggregations in which each spermiating male defends a nest, and ovulatory females move from nest to nest to mate. We postulated that milt compounds signal to ovulatory females the presence of spawning spermiating males. We determined that spermine, an odorous polyamine initially identified from human semen, is indeed a milt pheromone. At concentrations as low as 10-14 molar, spermine stimulated the lamprey olfactory system and attracted ovulatory females but did not attract males or pre-ovulatory females. We found spermine activated a trace amine-associated receptor (TAAR)-like receptor in the lamprey olfactory epithelium. A novel antagonist to that receptor nullified the attraction of ovulatory females to spermine. Our results elucidate a mechanism whereby a seminal plasma pheromone attracts ready-to-mate females and implicates a possible conservation of the olfactory detection of semen from jawless vertebrates to humans. Milt pheromones may also have management implications for sea lamprey populations.
DOI:10.1038/nchembio739URLPMID:16408070 [本文引用: 1]
The sea lamprey is an ancient, parasitic fish that invaded the Great Lakes a century ago, where it triggered the collapse of many fisheries. Like many fishes, this species relies on chemical cues to mediate key aspects of its life, including migration and reproduction. Here we report the discovery of a multicomponent steroidal pheromone that is released by stream-dwelling larval lamprey and guides adults to spawning streams. We isolated three compounds with pheromonal activity (in submilligram quantities from 8,000 l of larval holding water) and deduced their structures. The most important compound contains an unprecedented 1-(3-aminopropyl)pyrrolidin-2-one subunit and is related to squalamine, an antibiotic produced by sharks. We verified its structure by chemical synthesis; it attracts adult lamprey at very low (subpicomolar) concentrations. The second component is another new sulfated steroid and the third is petromyzonol sulfate, a known lamprey-specific bile acid derivative. This mixture is the first migratory pheromone identified in a vertebrate and is being investigated for use in lamprey control.
DOI:10.1101/pdb.prot5117URLPMID:20147012 [本文引用: 1]
This protocol describes how to generate high-titer lentivirus for the production of transgenic Japanese quail. The virus is pseudotyped with vesicular stomatitis virus with the envelope G glycoprotein (VSV-g), which gives a broad infectious range and allows concentration of viral supernatants by ultracentrifugation. Using this method, we typically produce titers >1 x 10(8) transforming units (TU)/mL and recommend using a virus with a titer at least this high for in vivo work.
DOI:10.3724/SP.J.1005.2012.00465URL [本文引用: 1]
DOI:10.3724/SP.J.1005.2012.00465URL [本文引用: 1]
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DOI:10.7554/eLife.16472URLPMID:27635636 [本文引用: 1]
Animals integrate the different senses to facilitate event-detection for navigation in their environment. In vertebrates, the optic tectum (superior colliculus) commands gaze shifts by synaptic integration of different sensory modalities. Recent works suggest that tectum can elaborate gaze reorientation commands on its own, rather than merely acting as a relay from upstream/forebrain circuits to downstream premotor centers. We show that tectal circuits can perform multisensory computations independently and, hence, configure final motor commands. Single tectal neurons receive converging visual and electrosensory inputs, as investigated in the lamprey - a phylogenetically conserved vertebrate. When these two sensory inputs overlap in space and time, response enhancement of output neurons occurs locally in the tectum, whereas surrounding areas and temporally misaligned inputs are inhibited. Retinal and electrosensory afferents elicit local monosynaptic excitation, quickly followed by inhibition via recruitment of GABAergic interneurons. Multisensory inputs can thus regulate event-detection within tectum through local inhibition without forebrain control.
DOI:10.1016/j.cub.2019.01.004URLPMID:30713108 [本文引用: 1]
Dopaminergic neurons in the substantia nigra (SNc) innervate both striatum and the superior colliculus in mammals, as well as its homolog the optic tectum in lampreys, belonging to the oldest group of living vertebrates [1-3]. In the lamprey, we have previously shown that the same neuron sends axonal branches to both striatum and the optic tectum [3]. Here, we show that most neurons in the lamprey SNc and ventral tegmental area (VTA) (also referred to as the nucleus of the posterior tuberculum) express not only tyrosine hydroxylase (TH), in lamprey a marker of dopaminergic neurons [4], but also the vesicular glutamate transporter (vGluT), suggesting that glutamate is a co-transmitter. Remarkably, the axonal branches that project to striatum elicit both dopaminergic and glutamatergic synaptic effects on striatal neurons, whereas the axonal projections to the optic tectum only evoke dopaminergic effects. Thus, axonal branches from the same neuron can use two transmitters in one branch and only one in the other. Previous studies suggest that, along an individual dopaminergic axon, there can be microdomains of either TH or vGluT [5-8]. In addition, the present results demonstrate that entire axonal branches to one target structure can differ from that of branches to another target, both originating from the same dopamine neuron. This implies that a given dopamine neuron can exert different effects on two different target structures. The combined release of dopamine and glutamate may be appropriate in striatum, whereas the effects exerted on the tectal motor center may be better served with a selective dopaminergic modulation.
DOI:10.1007/978-3-319-20819-0_8URLPMID:26537382 [本文引用: 1]
Jawless vertebrates represented by lampreys and hagfish mount antigen-specific immune responses using variable lymphocyte receptors. These receptors generate diversity comparable to that of T-cell and B-cell receptors by assembling multiple leucine-rich repeat modules with highly variable sequences. Although it is true that jawed and jawless vertebrates have structurally unrelated antigen receptors, their adaptive immune systems have much in common. Most notable is the conservation of lymphocyte lineages. It appears that specialized lymphocyte lineages emerged in a common vertebrate ancestor and that jawed and jawless vertebrates co-opted different antigen receptors within the context of such lymphocyte lineages.
DOI:10.1073/pnas.1704457114URLPMID:28784804 [本文引用: 1]
ParaHox genes (Gsx, Pdx, and Cdx) are an ancient family of developmental genes closely related to the Hox genes. They play critical roles in the patterning of brain and gut. The basal chordate, amphioxus, contains a single ParaHox cluster comprising one member of each family, whereas nonteleost jawed vertebrates contain four ParaHox genomic loci with six or seven ParaHox genes. Teleosts, which have experienced an additional whole-genome duplication, contain six ParaHox genomic loci with six ParaHox genes. Jawless vertebrates, represented by lampreys and hagfish, are the most ancient group of vertebrates and are crucial for understanding the origin and evolution of vertebrate gene families. We have previously shown that lampreys contain six Hox gene loci. Here we report that lampreys contain only two ParaHox gene clusters (designated as alpha- and beta-clusters) bearing five ParaHox genes (Gsxalpha, Pdxalpha, Cdxalpha, Gsxbeta, and Cdxbeta). The order and orientation of the three genes in the alpha-cluster are identical to that of the single cluster in amphioxus. However, the orientation of Gsxbeta in the beta-cluster is inverted. Interestingly, Gsxbeta is expressed in the eye, unlike its homologs in jawed vertebrates, which are expressed mainly in the brain. The lamprey Pdxalpha is expressed in the pancreas similar to jawed vertebrate Pdx genes, indicating that the pancreatic expression of Pdx was acquired before the divergence of jawless and jawed vertebrate lineages. It is likely that the lamprey Pdxalpha plays a crucial role in pancreas specification and insulin production similar to the Pdx of jawed vertebrates.
DOI:10.1038/s41559-018-0526-2URLPMID:29610468 [本文引用: 1]
Hox genes exert fundamental roles for proper regional specification along the main rostro-caudal axis of animal embryos. They are generally expressed in restricted spatial domains according to their position in the cluster (spatial colinearity)-a feature that is conserved across bilaterians. In jawed vertebrates (gnathostomes), the position in the cluster also determines the onset of expression of Hox genes (a feature known as whole-cluster temporal colinearity (WTC)), while in invertebrates this phenomenon is displayed as a subcluster-level temporal colinearity. However, little is known about the expression profile of Hox genes in jawless vertebrates (cyclostomes); therefore, the evolutionary origin of WTC, as seen in gnathostomes, remains a mystery. Here, we show that Hox genes in cyclostomes are expressed according to WTC during development. We investigated the Hox repertoire and Hox gene expression profiles in three different species-a hagfish, a lamprey and a shark-encompassing the two major groups of vertebrates, and found that these are expressed following a whole-cluster, temporally staggered pattern, indicating that WTC has been conserved during the past 500 million years despite drastically different genome evolution and morphological outputs between jawless and jawed vertebrates.
DOI:10.1111/brv.12403URLPMID:29488315 [本文引用: 1]
Lampreys, which represent the oldest group of living vertebrates (cyclostomes), show unique eye development. The lamprey larva has only eyespot-like immature eyes beneath a non-transparent skin, whereas after metamorphosis, the adult has well-developed image-forming camera eyes. To establish a functional visual system, well-organised visual centres as well as motor components (e.g. trunk muscles for locomotion) and interactions between them are needed. Here we review the available knowledge concerning the structure, function and development of the different parts of the lamprey visual system. The lamprey exhibits stepwise development of the visual system during its life cycle. In prolarvae and early larvae, the 'primary' retina does not have horizontal and amacrine cells, but does have photoreceptors, bipolar cells and ganglion cells. At this stage, the optic nerve projects mostly to the pretectum, where the dendrites of neurons in the nucleus of the medial longitudinal fasciculus (nMLF) appear to receive direct visual information and send motor outputs to the neck and trunk muscles. This simple neural circuit may generate negative phototaxis. Through the larval period, the lateral region of the retina grows again to form the 'secondary' retina and the topographic retinotectal projection of the optic nerve is formed, and at the same time, the extra-ocular muscles progressively develop. During metamorphosis, horizontal and amacrine cells differentiate for the first time, and the optic tectum expands and becomes laminated. The adult lamprey then has a sophisticated visual system for image-forming and visual decision-making. In the adult lamprey, the thalamic pathway (retina-thalamus-cortex/pallium) also transmits visual stimuli. Because the primary, simple light-detecting circuit in larval lamprey shares functional and developmental similarities with that of protochordates (amphioxus and tunicates), the visual development of the lamprey provides information regarding the evolutionary transition of the vertebrate visual system from the protochordate-type to the vertebrate-type.
DOI:10.1126/science.1162484URLPMID:18818359 [本文引用: 2]
Variable lymphocyte receptors (VLRs) rather than antibodies play the primary role in recognition of antigens in the adaptive immune system of jawless vertebrates. Combinatorial assembly of leucine-rich repeat (LRR) gene segments achieves the required repertoire for antigen recognition. We have determined a crystal structure for a VLR-antigen complex, VLR RBC36 in complex with the H-antigen trisaccharide from human blood type O erythrocytes, at 1.67 angstrom resolution. RBC36 binds the H-trisaccharide on the concave surface of the LRR modules of the solenoid structure where three key hydrophilic residues, multiple van der Waals interactions, and the highly variable insert of the carboxyl-terminal LRR module determine antigen recognition and specificity. The concave surface assembled from the most highly variable regions of the LRRs, along with diversity in the sequence and length of the highly variable insert, can account for the recognition of diverse antigens by VLRs.
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DOI:10.1038/ng.2568URLPMID:23435085 [本文引用: 2]
Lampreys are representatives of an ancient vertebrate lineage that diverged from our own approximately 500 million years ago. By virtue of this deeply shared ancestry, the sea lamprey (P. marinus) genome is uniquely poised to provide insight into the ancestry of vertebrate genomes and the underlying principles of vertebrate biology. Here, we present the first lamprey whole-genome sequence and assembly. We note challenges faced owing to its high content of repetitive elements and GC bases, as well as the absence of broad-scale sequence information from closely related species. Analyses of the assembly indicate that two whole-genome duplications likely occurred before the divergence of ancestral lamprey and gnathostome lineages. Moreover, the results help define key evolutionary events within vertebrate lineages, including the origin of myelin-associated proteins and the development of appendages. The lamprey genome provides an important resource for reconstructing vertebrate origins and the evolutionary events that have shaped the genomes of extant organisms.
DOI:10.1093/biosci/biv139URLPMID:26951616 [本文引用: 1]
Lampreys, one of the two surviving groups of ancient vertebrates, have become important models for study in diverse fields of biology. Lampreys (of which there are approximately 40 species) are being studied, for example, (a) to control pest sea lamprey in the North American Great Lakes and to restore declining populations of native species elsewhere; (b) in biomedical research, focusing particularly on the regenerative capability of lampreys; and (c) by developmental biologists studying the evolution of key vertebrate characters. Although a lack of genetic resources has hindered research on the mechanisms regulating many aspects of lamprey life history and development, formerly intractable questions are now amenable to investigation following the recent publication of the sea lamprey genome. Here, we provide an overview of the ways in which genomic tools are currently being deployed to tackle diverse research questions and suggest several areas that may benefit from the availability of the sea lamprey genome.
URLPMID:22825976 [本文引用: 2]
Spinal cord injuries are an important sanitary and economical problem for the society. In mammals, including humans, a traumatic injury to the spinal cord leads to a loss of motor and sensorial function, which is irreversible due to the low regenerative ability of the central nervous system. In contrast to mammals, functional recovery occurs spontaneously after a complete spinal cord transection in lampreys. Functional recovery occurs because in these animals about 50% of the reticulospinal axons regenerate after injury and also because of the occurrence of processes of reorganization and plasticity of the spinal circuits. In this review, we first analyze the characteristics and regeneration ability of lampreys as compared to mammals. Then, we compile the knowledge about the process of recovery after a spinal cord injury acquired in studies using the lampreys as animal model and finally we provide some general perspectives about the molecular processes implicated in regeneration that can be investigated in a very advantageous way in this animal model and which knowledge could allow to develop new therapies for patients suffering spinal cord injury.
URLPMID:8273515 [本文引用: 2]
The preceding pages have described an organism that is far removed from mammals on the taxonomic scale of vertebrates but one that has proven to have a unique and most useful system for studies of liver function and, in particular, bile product transport and excretion. It is also an organism in which iron loading can be studied in the liver and other organs and tissues. Many of the events that occur in this animal during its life cycle with regard to bile pigment metabolism as normal programmed phenomena are unparalleled among the vertebrates. In the larval (ammocoete) period of lampreys, there is an intrahepatic gallbladder and a biliary tree that is well equipped for the storage, transport, and elimination of bile products into the intestine for ultimate excretion with the feces. The importance of the patency of these bile ducts to bile excretion is illustrated in one species of lampreys in which the bile ducts of young ammocoetes become infested with larval nematodes to a degree that bile pigment regurgitation into the blood results in a green serum that is identified as biliverdin. Despite having serum levels of biliverdin that would be toxic to humans, these individuals live a complete larval life. The larvae of all lamprey species undergo a phase of metamorphosis in which they transform into adults. During this phase the larval gallbladder, the bile canaliculi of the hepatocytes, and all the intrahepatic bile ducts completely regress in a developmental process called lamprey biliary atresia. The epithelium of the extrahepatic common bile duct transforms and expands into a caudal portion of the endocrine pancreas of the adult. Many of the events of lamprey biliary atresia resemble events occurring during experimental and pathological conditions of mammalian cholestasis, including disruption to the bile-blood barrier (intercellular junctions), accumulation of bile components in the cytoplasmic inclusions, and alteration of the distribution of membrane enzymes in hepatocytes. Regression of the bile ducts and ductules is accompanied by a periductular fibrosis that seems to be a product of activity by lipocytes (Ito cells). The regurgitation of bile products into the interstitial tissue of the liver during early biliary atresia may be the stimulus for both inflammatory (granulomatous) and autoimmune responses. There are no bile ducts in adults lampreys, yet they seem to show no immediate consequences of the absence of an exocrine mechanism for the elimination of bile products.(ABSTRACT TRUNCATED AT 400 WORDS)
DOI:10.1073/pnas.0405529101URLPMID:15328402 [本文引用: 1]
All jawed vertebrates have highly diverse lymphocyte receptors, which allow discrimination between self and nonself antigens as well as the recognition of potential pathogens. Key elements of the anticipatory recombinatorial immune system in jawed vertebrates are the TCR, Ig, and MHC genes, but their ancestral genes have not been found in more basal vertebrates. In this study, we extended our analysis of the transcriptome of lymphocyte-like cells in the lamprey to identify the TCR-like and CD4-like genes. The structural features of these genes and their preferential expression in lymphocytes make them attractive candidates for ancestral TCR and CD4 genes. The TCR-like gene contains both V (variable) and J (joining) sequences in its first exon and exists as a single-copy gene that is invariant. Thus, the TCR-like gene cannot account for the receptor diversity that is required for the immune responses reported for lamprey, but it could have been easily modified to serve as an evolutionary precursor of modern TCR and Ig genes.
DOI:10.1038/nature08068URLPMID:19474790 [本文引用: 2]
Jawless vertebrates use variable lymphocyte receptors (VLR) comprised of leucine-rich-repeat (LRR) segments as counterparts of the immunoglobulin-based receptors that jawed vertebrates use for antigen recognition. Highly diverse VLR genes are somatically assembled by the insertion of variable LRR sequences into incomplete germline VLRA and VLRB genes. Here we show that in sea lampreys (Petromyzon marinus) VLRA and VLRB anticipatory receptors are expressed by separate lymphocyte populations by monoallelic VLRA or VLRB assembly, together with expression of cytosine deaminase 1 (CDA1) or 2 (CDA2), respectively. Distinctive gene expression profiles for VLRA(+) and VLRB(+) lymphocytes resemble those of mammalian T and B cells. Although both the VLRA and the VLRB cells proliferate in response to antigenic stimulation, only the VLRB lymphocytes bind native antigens and differentiate into VLR antibody-secreting cells. Conversely, VLRA lymphocytes respond preferentially to a classical T-cell mitogen and upregulate the expression of the pro-inflammatory cytokine genes interleukin-17 (IL-17) and macrophage migration inhibitory factor (MIF). The finding of T-like and B-like lymphocytes in lampreys offers new insight into the evolution of adaptive immunity.
DOI:10.1038/ni1562URLPMID:18246071 [本文引用: 1]
Lamprey and hagfish, the living representatives of jawless vertebrates, use genomic leucine-rich-repeat cassettes for the combinatorial assembly of diverse antigen receptor genes encoding variable lymphocyte receptors of two types: VLRA and VLRB. We describe here the VLRB-bearing lineage of lymphocytes in sea lamprey. These cells responded to repetitive carbohydrate or protein determinants on bacteria or mammalian cells with lymphoblastoid transformation, proliferation and differentiation into plasmacytes that secreted multimeric antigen-specific VLRB antibodies. Lacking a thymus and the ability to respond to soluble protein antigens, lampreys seem to have evolved a B cell-like system for adaptive humoral responses.
DOI:10.1007/978-3-319-20819-0_8URLPMID:26537382 [本文引用: 1]
Jawless vertebrates represented by lampreys and hagfish mount antigen-specific immune responses using variable lymphocyte receptors. These receptors generate diversity comparable to that of T-cell and B-cell receptors by assembling multiple leucine-rich repeat modules with highly variable sequences. Although it is true that jawed and jawless vertebrates have structurally unrelated antigen receptors, their adaptive immune systems have much in common. Most notable is the conservation of lymphocyte lineages. It appears that specialized lymphocyte lineages emerged in a common vertebrate ancestor and that jawed and jawless vertebrates co-opted different antigen receptors within the context of such lymphocyte lineages.
DOI:10.1126/science.1119420URLPMID:16373579 [本文引用: 1]
Instead of the immunoglobulin-type antigen receptors of jawed vertebrates, jawless fish have variable lymphocyte receptors (VLRs), which consist of leucine-rich repeat (LRR) modules. Somatic diversification of the VLR gene is shown here to occur through a multistep assembly of LRR modules randomly selected from a large bank of flanking cassettes. The predicted concave surface of the VLR is lined with hypervariable positively selected residues, and computational analysis suggests a repertoire of about 10(14) unique receptors. Lamprey immunized with anthrax spores responded with the production of soluble antigen-specific VLRs. These findings reveal that two strikingly different modes of antigen recognition through rearranged lymphocyte receptors have evolved in the jawless and jawed vertebrates.
DOI:10.1074/jbc.M608471200URLPMID:17192264 [本文引用: 1]
Variable lymphocyte receptors (VLRs) are recently discovered leucine-rich repeat (LRR) family proteins that mediate adaptive immune responses in jawless fish. Phylogenetically it is the oldest adaptive immune receptor and the first one with a non-immunoglobulin fold. We present the crystal structures of one VLR-A and two VLR-B clones from the inshore hagfish. The hagfish VLRs have the characteristic horseshoe-shaped structure of LRR family proteins. The backbone structures of their LRR modules are highly homologous, and the sequence variation is concentrated on the concave surface of the protein. The conservation of key residues suggests that our structures are likely to represent the LRR structures of the entire repertoire of jawless fish VLRs. The analysis of sequence variability, prediction of protein interaction surfaces, amino acid composition analysis, and structural comparison with other LRR proteins suggest that the hypervariable concave surface is the most probable antigen binding site of the VLR.
DOI:10.1073/pnas.0711619105URLPMID:18238899 [本文引用: 1]
Adaptive immunity in jawless vertebrates (lamprey and hagfish) is mediated by lymphocytes that undergo combinatorial assembly of leucine-rich repeat (LRR) gene segments to create a diverse repertoire of variable lymphocyte receptor (VLR) genes. Immunization with particulate antigens induces VLR-B-bearing lymphocytes to secrete antigen-specific VLR-B antibodies. Here, we describe the production of recombinant VLR-B antibodies specific for BclA, a major coat protein of Bacillus anthracis spores. The recombinant VLR-B antibodies possess 8-10 uniform subunits that collectively bind antigen with high avidity. Sequence analysis, mutagenesis, and modeling studies show that antigen binding involves residues in the beta-sheets lining the VLR-B concave surface. EM visualization reveals tetrameric and pentameric molecules having a central core and highly flexible pairs of stalk-region
DOI:10.1146/annurev-immunol-020711-075038URL [本文引用: 1]
DOI:10.1038/nature12467URL [本文引用: 1]
Jawed vertebrates (gnathostomes) and jawless vertebrates (cyclostomes) have different adaptive immune systems(1,2). Gnathostomes use T- and B-cell antigen receptors belonging to the immunoglobulin superfamily(3,4). Cyclostomes, the lampreys and hagfish, instead use leucine-rich repeat proteins to construct variable lymphocyte receptors (VLRs), two types of which, VLRA and VLRB, are reciprocally expressed by lymphocytes resembling gnathostome T and B cells(5-7). Here we define another lineage of T-cell-like lymphocytes that express the recently identified VLRC receptors(8,9). Both VLRC+ and VLRA(+) lymphocytes express orthologues of genes that gnathostome gamma delta and alpha beta T cells use for their differentiation, undergo VLRC and VLRA assembly and repertoire diversification in the 'thymoid' gill region, and express their VLRs solely as cell-surface proteins. Our findings suggest that the genetic programmes for two primordial T-cell lineages and a prototypic B-cell lineage were already present in the last common vertebrate ancestor approximately 500 million years ago. We propose that functional specialization of distinct T-cell-like lineages was an ancient feature of a primordial immune system.
DOI:10.1073/pnas.0904443106URLPMID:19625627 [本文引用: 1]
Lamprey are members of the ancestral vertebrate taxon (jawless fish), which evolved rearranging antigen receptors convergently with the jawed vertebrates. But instead of Ig superfamily domains, lamprey variable lymphocyte receptors (VLRs) consist of highly diverse leucine-rich repeats. Although VLRs represent the only known adaptive immune system not based on Ig, little is known about their antigen-binding properties. Here we report robust plasma VLRB responses of lamprey immunized with hen egg lysozyme and beta-galactosidase (beta-gal), demonstrating adaptive immune responses against soluble antigens. To isolate monoclonal VLRs, we constructed large VLR libraries from antigen-stimulated and naive animals in a novel yeast surface-display vector, with the VLR C-terminally fused to the yeast Flo1p surface anchor. We cloned VLRB binders of lysozyme, beta-gal, cholera toxin subunit B, R-phycoerythrin, and B-trisaccharide antigen, with dissociation constants up to the single-digit picomolar range, equivalent to those of high-affinity IgG antibodies. We also isolated from a single lamprey 13 anti-lysozyme VLRA clones with affinities ranging from low nanomolar to mid-picomolar. All of these VLRA clones were closely related in sequence, differing at only 15 variable codon positions along the 244-residue VLR diversity region, which augmented antigen-binding affinity up to 100-fold. Thus, VLRs can provide a protective humoral antipathogen shield. Furthermore, the broad range of nominal antigens that VLRs can specifically bind, and the affinities achieved, indicate a functional parallelism between LRR-based and Ig-based antibodies. VLRs may be useful natural single-chain alternatives to conventional antibodies for biotechnology applications.
DOI:10.4049/jimmunol.1900026URLPMID:31666307 [本文引用: 1]
The TNF superfamily ligands BAFF and APRIL interact with three receptors, BAFFR, BCMA, and TACI, to play discrete and crucial roles in regulating B cell selection and homeostasis in mammals. The interactions between these ligands and receptors are both specific and redundant: BAFFR binds BAFF, whereas BCMA and TACI bind to either BAFF or APRIL. In a previous phylogenetic inquiry, we identified and characterized a BAFF-like gene in lampreys, which, with hagfish, are the only extant jawless vertebrates, both of which have B-like and T-like lymphocytes. To gain insight into lymphocyte regulation in jawless vertebrates, in this study we identified two BCMA-like genes in lampreys, BCMAL1 and BCMAL2, which were found to be preferentially expressed by B-like lymphocytes. In vitro analyses indicated that the lamprey BAFF-like protein can bind to a BCMA-like receptor Ig fusion protein and to both BCMAL1- and BCMAL2-transfected cells. Discriminating regulatory roles for the two BCMA-like molecules are suggested by their differential expression before and after activation of the B-like lymphocytes in lampreys. Our composite results imply that BAFF-based mechanisms for B cell regulation evolved before the divergence of jawed and jawless vertebrates.
DOI:10.3724/SP.J.1005.2009.00969URL [本文引用: 1]
DOI:10.3724/SP.J.1005.2009.00969URL [本文引用: 1]
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DOI:10.1016/j.immuni.2011.05.006URL [本文引用: 1]
Toll-like receptors (TLRs) are germline-encoded pattern recognition receptors (PRRs) that play a central role in host cell recognition and responses to microbial pathogens. TLR-mediated recognition of components derived from a wide range of pathogens and their role in the subsequent initiation of innate immune responses is widely accepted; however, the recent discovery of non-TLR PRRs, such as C-type lectin receptors, NOD-like receptors, and RIG-I-like receptors, suggests that many aspects of innate immunity are more sophisticated and complex. In this review, we will focus on the role played by TLRs in mounting protective immune responses against infection and their crosstalk with other PRRs with respect to pathogen recognition.
DOI:10.1038/icb.2016.18URLPMID:26860369 [本文引用: 1]
Innate immune cells recognize pathogens through pattern recognition receptors (PRRs), and activation of PRRs induces downstream signaling pathways to mount appropriate immune responses. Pathogens usually carry multiple ligands, which can simultaneously activate multiple PRRs. The cooperation of multiple PRRs and consequential crosstalk between their downstream pathways could enhance cytokine expression, which is required for effective immune responses. On the other hand, immune over-activation could also harm the host if immune homeostasis is not restored. Therefore, it is important to understand the mechanisms of PRR cooperation during an infection. As the best characterized PRRs, Toll-like receptors (TLRs) have an important role in pathogen recognition, and crosstalk among TLRs is common. In this review, we provide an update on the recent findings on the mechanisms of TLR cooperation. We summarize the known mechanisms and provide a future perspective on TLR crosstalk study, with a caution against the use of multiple TLR ligands as adjuvants in therapeutic strategies.
DOI:10.4049/jimmunol.1200876URLPMID:23293356 [本文引用: 1]
An alternative adaptive-immune system is present in the most basal vertebrates--lampreys and hagfish--the only surviving jawless vertebrates. These eel-like fish use leucine-rich repeat-based receptors for Ag recognition instead of the Ig-based receptors used in jawed vertebrates. We report that in Japanese lamprey (Lampetra japonica), variable lymphocyte receptor (VLR)B interacts with C1q and C3 proteins to mediate complement-dependent cytotoxicity for bacteria and tumor cells. The immune-based lysis involves deposition of VLRB and C1q-like protein complex on the surface of target cells, activation of C3, and ultimate disruption of cell wall integrity. The demonstration of functional interaction between VLRB and complement components in lamprey provides evidence for the emergence of cooperative innate and adaptive-immune responses at a pivotal point in vertebrate evolution, before or in parallel with the evolution of Ig-based Abs and the classical complement-activation pathway.
DOI:10.1093/abbs/gmu039URL [本文引用: 1]
DOI:10.1186/s40064-015-1270-6URLPMID:26543704 [本文引用: 1]
The supraneural body was identified in the adult lamprey, and its secretions induced the death of a variety of tumor cells but had no effect on normal cells. The cell secretions from different lamprey tissues were separated, and these secretions killed human tumor cells to varying degrees. The cell secretions induced remarkable cell morphological alterations such as cell blebbing, and the plasma membrane was destroyed by the secretions. In addition, the secretions induced morphological alterations of the mitochondria, cytoskeletal structure, and endoplasmic reticulum, eventually leading to cell death. These observations suggest the presence of a novel protein in the lamprey and the possibility of new applications for the protein in the medical field.
DOI:10.1186/s12964-017-0198-6URLPMID:29037260 [本文引用: 1]
BACKGROUND: In previous research, we found that cell secretion from the adult lamprey supraneural body tissues possesses cytocidal activity against tumor cells, but the protein with cytocidal activity was unidentified. METHODS: A novel lamprey immune protein (LIP) as defense molecule was first purified and identified in jawless vertebrates (cyclostomes) using hydroxyapatite column and Q Sepharose Fast Flow column. After LIP stimulation, morphological changes of tumor cells were analysed and measured whether in vivo or in vitro. RESULTS: LIP induces remarkable morphological changes in tumor cells, including cell blebbing, cytoskeletal alterations, mitochondrial fragmentation and endoplasmic reticulum vacuolation, and most of the cytoplasmic and organelle proteins are released following treatment with LIP. LIP evokes an elevation of intracellular calcium and inflammatory molecule levels. Our analysis of the cytotoxic mechanism suggests that LIP can upregulate the expression of caspase 1, RIPK1, RIP3 to trigger pyroptosis and necroptosis. To examine the effect of LIP in vivo, tumor xenograft experiments were performed, and the results indicated that LIP inhibits tumor growth without damage to mice. In addition, the cytotoxic action of LIP depended on the phosphatidylserine (PS) content of the cell membrane. CONCLUSIONS: These observations suggest that LIP plays a crucial role in tumor cell survival and growth. The findings will also help to elucidate the mechanisms of host defense in lamprey.
DOI:10.1016/j.fsi.2018.01.052URLPMID:29410138 [本文引用: 1]
The lamprey (Lampetra japonica), a representative of the jawless vertebrates, is the oldest extant species in the world. LIP-1, which has a jacalin-like domain and an aerolysin pore-forming domain, has previously been identified in Lampetra japonica. However, the structure and function of the LIP-1 protein have not been described. In this study, the LIP-1 gene was overexpressed in HeLa cells and H293T cells. The results showed that the overexpression of LIP-1 in HeLa cells significantly elevated LDH release (P<0.05), phosphatidylserine exposure and ROS accumulation. The overexpression of LIP-1 also had remarkable effects on the organelles in HeLa cells, while it had no effect on H293T cell organelles. Array data indicated that overexpression of LIP-1 primarily upregulated P53 signaling pathways in HeLa cells. Cell cycle assay results confirmed that LIP-1 caused arrest in the G2/M phase of the cell cycle in HeLa cells. In summary, our findings provide insights into the function and characterization of LIP-1 genes in vertebrates and establish the foundation for further research into the biological function of LIP-1. Our observations suggest that this lamprey protein has the potential for use in new applications in the medical field.
DOI:10.1186/s12964-019-0358-yURLPMID:31133022 [本文引用: 1]
BACKGROUND: In previous research, we found that lamprey immune protein (LIP) possessed cytocidal activity against tumor cells, but the mechanism of the selective recognition and killing of tumor cells by LIP was not identified. METHODS: Superresolution microscopy, crystallographic structural analysis, glycan chip assay, SPR experiments, FACS assays, computational studies and mass spectrometric analysis firmly establish the mode of action of LIP, which involves dual selective recognition and efficient binding. RESULTS: We determined the overall crystallographic structure of LIP at a resolution of 2.25 A. LIP exhibits an elongated structure with dimensions of 105 A x 30 A x 30 A containing an N-terminal lectin module and a C-terminal aerolysin module. Moreover, the Phe(209)-Gly(232) region is predicted to insert into the lipid bilayer to form a transmembrane beta-barrel, in which the hydrophobic residues face the lipid bilayer, and the polar residues constitute the hydrophilic lumen of the pore. We found that LIP is able to kill various human cancer cells with minimal effects on normal cells. Notably, by coupling biochemical and computational studies, we propose a hypothetical mechanism that involves dual selective recognition and efficient binding dependent on both N-linked glycans on GPI-anchored proteins (GPI-APs) and sphingomyelin (SM) in lipid rafts. Furthermore, specific binding of the lectin module with biantennary bisialylated nonfucosylated N-glycan or sialyl Lewis X-containing glycan structures on GPI-APs triggers substantial conformational changes in the aerolysin module, which interacts with SM, ultimately resulting in the formation of a membrane-bound oligomer in lipid rafts. CONCLUSIONS: LIP holds great potential for the application of a marine protein towards targeted cancer therapy and early diagnosis in humans.
DOI:10.1016/j.cub.2012.06.028URL [本文引用: 1]
The lamprey (Petromyzon marinus) undergoes developmentally programmed genome rearrangements that mediate deletion of similar to 20% of germline DNA from somatic cells during early embryogenesis. This genomic differentiation of germline and soma is intriguing, because the germline plays a unique biological role wherein it must possess the ability to undergo meiotic recombination and the capacity to differentiate into every cell type. These evolutionarily indispensable functions set the germline at odds with somatic tissues, because factors that promote recombination and pluripotency can potentially disrupt genome integrity or specification of cell fate when misexpressed in somatic cell lineages (e.g., in oncogenesis). Here, we describe the development of new genomic and transcriptomic resources for lamprey and use these to identify hundreds of genes that are targeted for programmed deletion from somatic cell lineages. Transcriptome sequencing and targeted validation studies further confirm that somatically deleted genes function both in adult (meiotic) germline and in the development of primordial germ cells during embryogenesis. Inferred functional information from deleted regions indicates that developmentally programmed rearrangement serves as a (perhaps ancient) biological strategy to ensure segregation of pluripotency functions to the germline, effectively eliminating the potential for somatic misexpression.
DOI:10.1371/journal.pgen.1006103URLPMID:27341395 [本文引用: 1]
The sea lamprey (Petromyzon marinus) represents one of the few vertebrate species known to undergo large-scale programmatic elimination of genomic DNA over the course of its normal development. Programmed genome rearrangements (PGRs) result in the reproducible loss of ~20% of the genome from somatic cell lineages during early embryogenesis. Studies of PGR hold the potential to provide novel insights related to the maintenance of genome stability during the cell cycle and coordination between mechanisms responsible for the accurate distribution of chromosomes into daughter cells, yet little is known regarding the mechanistic basis or cellular context of PGR in this or any other vertebrate lineage. Here we identify epigenetic silencing events that are associated with the programmed elimination of DNA and describe the spatiotemporal dynamics of PGR during lamprey embryogenesis. In situ analyses reveal that the earliest DNA methylation (and to some extent H3K9 trimethylation) events are limited to specific extranuclear structures (micronuclei) containing eliminated DNA. During early embryogenesis a majority of micronuclei (~60%) show strong enrichment for repressive chromatin modifications (H3K9me3 and 5meC). These analyses also led to the discovery that eliminated DNA is packaged into chromatin that does not migrate with somatically retained chromosomes during anaphase, a condition that is superficially similar to lagging chromosomes observed in some cancer subtypes. Closer examination of
DOI:10.1038/s41588-017-0036-1URLPMID:29358652 [本文引用: 1]
The sea lamprey (Petromyzon marinus) serves as a comparative model for reconstructing vertebrate evolution. To enable more informed analyses, we developed a new assembly of the lamprey germline genome that integrates several complementary data sets. Analysis of this highly contiguous (chromosome-scale) assembly shows that both chromosomal and whole-genome duplications have played significant roles in the evolution of ancestral vertebrate and lamprey genomes, including chromosomes that carry the six lamprey HOX clusters. The assembly also contains several hundred genes that are reproducibly eliminated from somatic cells during early development in lamprey. Comparative analyses show that gnathostome (mouse) homologs of these genes are frequently marked by polycomb repressive complexes (PRCs) in embryonic stem cells, suggesting overlaps in the regulatory logic of somatic DNA elimination and bivalent states that are regulated by early embryonic PRCs. This new assembly will enhance diverse studies that are informed by lampreys' unique biology and evolutionary/comparative perspective.
DOI:10.1085/jgp.35.1.45URLPMID:14873920 [本文引用: 1]
The blood hemoglobin of the sea lamprey presents a curious mixture of primitive and highly specialized properties. Like muscle hemoglobin, it has a molecular weight of about 17,000, and apparently contains a single heme. Its isoelectric point is like that of a typical invertebrate hemoglobin. Its amino acid composition is partly characteristic of invertebrate) partly of vertebrate hemoglobins (Pedersen; Roche and Fontaine). In the present experiments, the oxygen equilibrium curve of this pigment was measured at several pH's. As expected, it is a rectangular hyperbola, the first such function to be observed in a vertebrate blood hemoglobin. Other hemoglobins known to possess this type of oxygen dissociation curve-those of vertebrate muscle, the worm Nippostrongylus, and the bot-fly larva-appear to serve primarily the function of oxygen storage rather than transport. Lamprey hemoglobin on the contrary is an efficient oxygen-transporting agent. It achieves this status by having, unlike muscle hemoglobin, a relatively low oxygen affinity, and a very large Bohr effect. In these properties it rivals the most effective vertebrate blood hemoglobins.
DOI:10.1152/ajplegacy.1962.203.5.964URLPMID:22103034 [本文引用: 1]
Blood coagulation systems in cyclostome, elasmobranch, and teleost fish were studied and compared. The plasma of all these fish contained a fibrinogen molecule, capable of being clotted by human thrombin, and a prothrombin molecule, capable of being converted into thrombin which could hydrolyze p-tosyl l-arginine methyl ester. The prothrombin activity could be adsorbed on barium sulfate. Accurate assessment of prothrombin conversion factors is confounded by the
DOI:10.1006/bcmd.2002.0534URLPMID:12482404 [本文引用: 1]
It is not clear how the complex mammalian coagulation pathways evolved from an entirely dissimilar invertebrate coagulation cascade. Comprehensive analysis of pro-coagulant factors and their regulators is lacking in early vertebrates to discern the mechanism of evolution of these genes from the invertebrates. To elucidate the coagulation pathways found in early vertebrates, zebrafish cDNAs/gene orthologues for major coagulant, anticoagulant, and fibrinolytic proteins were identified and characterized by homology to mammalian sequences. We found that zebrafish carry all hemostatic genes present in mammals, providing evidence that the coagulation system of teleosts is nearly identical to mammals. Zebrafish factor VII and X genes were identified and analyzed to reveal a novel factor VII-like gene flanked by the factor VII and factor X genes. This gene encodes a protein homologous to factor VII, but lacks critical residues for factor VII activity. Expression of the factor VII-like protein (named factor VIIi) demonstrated that it functions as an inhibitor of blood coagulation in biochemical assays using zebrafish or human plasmas. Analysis of intergenic DNA between the zebrafish VII/VIIi/X gene cluster and a Drosophila trypsin gene cluster revealed significant homology, and based upon these data, we propose a model for a rapid evolution of coagulation factors from the invertebrates.
DOI:10.1007/s00239-015-9701-0URLPMID:26437661 [本文引用: 1]
Lampreys and hagfish are the earliest diverging of extant vertebrates and are obvious targets for investigating the origins of complex biochemical systems found in mammals. Currently, the simplest approach for such inquiries is to search for the presence of relevant genes in whole genome sequence (WGS) assemblies. Unhappily, in the past a high-quality complete genome sequence has not been available for either lampreys or hagfish, precluding the possibility of proving gene absence. Recently, improved but still incomplete genome assemblies for two species of lamprey have been posted, and, taken together with an extensive collection of short sequences in the NCBI trace archive, they have made it possible to make reliable counts for specific gene families. Particularly, a multi-source tactic has been used to study the lamprey blood clotting system with regard to the presence and absence of genes known to occur in higher vertebrates. As was suggested in earlier studies, lampreys lack genes for coagulation factors VIII and IX, both of which are critical for the
DOI:10.1038/nature05436URLPMID:17187056 [本文引用: 1]
The genetic mechanisms regulating tetrapod limb development are well characterized, but how they were assembled during evolution and their function in basal vertebrates is poorly understood. Initial studies report that chondrichthyans, the most primitive extant vertebrates with paired appendages, differ from ray-finned fish and tetrapods in having Sonic hedgehog (Shh)-independent patterning of the appendage skeleton. Here we demonstrate that chondrichthyans share patterns of appendage Shh expression, Shh appendage-specific regulatory DNA, and Shh function with ray-finned fish and tetrapods. These studies demonstrate that some aspects of Shh function are deeply conserved in vertebrate phylogeny, but also highlight how the evolution of Shh regulation may underlie major morphological changes during appendage evolution.
DOI:10.1093/hmg/ddg180URLPMID:12837695 [本文引用: 1]
Unequivocal identification of the full composition of a gene is made difficult by the cryptic nature of regulatory elements. Regulatory elements are notoriously difficult to locate and may reside at considerable distances from the transcription units on which they operate and, moreover, may be incorporated into the structure of neighbouring genes. The importance of regulatory mutations as the basis of human abnormalities remains obscure. Here, we show that the chromosome 7q36 associated preaxial polydactyly, a frequently observed congenital limb malformation, results from point mutations in a Shh regulatory element. Shh, normally expressed in the ZPA posteriorly in the limb bud, is expressed in an additional ectopic site at the anterior margin in mouse models of PPD. Our investigations into the basis of the ectopic Shh expression identified the enhancer element that drives normal Shh expression in the ZPA. The regulator, designated ZRS, lies within intron 5 of the Lmbr1 gene 1 Mb from the target gene Shh. The ZRS drives the early spatio-temporal expression pattern in the limb of tetrapods. Despite the morphological differences between limbs and fins, an equivalent regulatory element is found in fish. The ZRS contains point mutations that segregate with polydactyly in four unrelated families with PPD and in the Hx mouse mutant. Thus point mutations residing in long-range regulatory elements are capable of causing congenital abnormalities, and possess the capacity to modify gene activity such that a novel gamut of abnormalities is detected.
DOI:10.1242/dev.01613URLPMID:15677727 [本文引用: 1]
Mutations in a conserved non-coding region in intron 5 of the Lmbr1 locus, which is 1 Mb away from the sonic hedgehog (Shh) coding sequence, are responsible for mouse and human preaxial polydactyly with mirror-image digit duplications. In the mouse mutants, ectopic Shh expression is observed in the anterior mesenchyme of limb buds. Furthermore, a transgenic reporter gene flanked with this conserved non-coding region shows normal polarized expression in mouse limb buds. This conserved sequence has therefore been proposed to act as a long-range, cis-acting regulator of limb-specific Shh expression. Previous phylogenetic studies have also shown that this sequence is highly conserved among tetrapods, and even in teleost fishes. Paired fins of teleost fishes and tetrapod limbs have evolved from common ancestral appendages, and polarized Shh expression is commonly observed in fins. In this study, we first show that this conserved sequence motif is also physically linked to the Shh coding sequence in a teleost fish, the medaka, by homology search of a newly available genomic sequence database. Next, we show that deletion of this conserved intronic sequence by targeted mutation in the mouse results in a complete loss of Shh expression in the limb bud and degeneration of skeletal elements distal to the stylopod/zygopod junction. This sequence contains a major limb-specific Shh enhancer that is necessary for distal limb development. These results suggest that the conserved intronic sequence evolved in a common ancestor of fishes and tetrapods to control fin and limb development.
DOI:10.1016/j.fsi.2019.11.037URLPMID:31759079 [本文引用: 1]
Tumor necrosis factor receptor superfamilies (TNFRSF) are one of essential cytokines and can trigger inflammation, apoptosis, participating lymphocyte homeostasis and tissue development in vertebrates. To gain insights into the evolution and characterization of tnfr genes in lamprey, a jawless vertebrate, we performed a genome-wide and transcriptome survey and identified 7 tnfr genes in the lamprey (Lethenteron reissneri) database. Based on the molecular phylogenetic analysis, 7 L-tnfr genes are divided into three different clusters, and multiple members of tnfr genes family have appeared in lamprey. Meanwhile, protein domains and motifs analysis reveals that TNFRSF are conserved and have typical cysteine-rich domains (CRDs). Synteny results indicates that the L-tnfr neighborhood genes have taken place great changes compared to jawed vertebrates. Real-time quantitative results demonstrate that tnfr gene family plays an important role in the immune defense. This study has a new understanding for origin and evolution of the tnfr gene family in different vertebrates.
DOI:10.1016/j.brainresbull.2007.10.057URLPMID:18331874 [本文引用: 1]
Vertebrate brains exhibit remarkable diversity in each animal group, reflecting evolutionary changes at the molecular-level developmental program of the nervous system that vertebrates have experienced. We focused on the developmental morphological plan of the brain to understand the evolutionary scenario that led to the above diversity. By comparing the organization of the brain of non-vertebrate chordates, cyclostomes and gnathostomes, a step-wise modification of brain patterning programs becomes apparent. Furthermore, by labeling the lamprey oral region, the somatotopic projections of the trigeminal nerve that enter into the hindbrain become visible. Finally, by combining the knowledge on rhombomere segments and neuronal projections, the evolutionary relationship between somatotopy and brain segmentation are discussed.
DOI:10.1111/j.1749-6632.1977.tb41902.xURLPMID:280225 [本文引用: 1]
[本文引用: 1]
DOI:10.1016/j.cub.2007.03.044URLPMID:17580069 [本文引用: 1]
DOI:10.1038/s41559-020-1137-2URLPMID:32203472 [本文引用: 2]
Amniotes, such as mammals and reptiles, have vision and other senses represented in the pallium, whereas anamniotes, such as amphibians, fish and cyclostomes (including lampreys), which diverged much earlier, were historically thought to process olfactory information predominantly or even exclusively in the pallium. Here, we show that there is a separate visual area with retinotopic representation, and that somatosensory information from the head and trunk is represented in an adjacent area in the lamprey pallial cortex (lateral pallium). These cortical sensory areas flank a non-primary-sensory motor area. Both vision and somatosensation are relayed via the thalamus. These findings suggest that the basic sensorimotor representation of the mammalian neocortex, as well as the sensory thalamocortical relay, had already evolved in the last common ancestor of cyclostomes and gnathostomes around 560 million years ago.
DOI:10.1146/annurev.neuro.31.060407.125547URLPMID:18558853 [本文引用: 1]
Each of the descending pathways involved in motor control has a number of anatomical, molecular, pharmacological, and neuroinformatic characteristics. They are differentially involved in motor control, a process that results from operations involving the entire motor network rather than from the brain commanding the spinal cord. A given pathway can have many functional roles. This review explores to what extent descending pathways are highly conserved across species and concludes that there are actually rather widespread species differences, for example, in the transmission of information from the corticospinal tract to upper limb motoneurons. The significance of direct, cortico-motoneuronal (CM) connections, which were discovered a little more than 50 years ago, is reassessed. I conclude that although these connections operate in parallel with other less direct linkages to motoneurons, CM influence is significant and may subserve some special functions including adaptive motor behaviors involving the distal extremities.
DOI:10.1016/j.cub.2014.12.013URLPMID:25619762 [本文引用: 1]
BACKGROUND: The frontal lobe control of movement in mammals has been thought to be a specific function primarily related to the layered neocortex with its efferent connections. In contrast, we now show that the same basic organization is present even in one of the phylogenetically oldest vertebrates, the lamprey. RESULTS: Stimulation of specific sites in the pallium/cortex evokes eye, trunk, locomotor, or oral movements. The pallial projection neurons target brainstem motor centers and basal ganglia subnuclei and have prominent dendrites extending into the outer molecular layer. They exhibit the characteristic features of pyramidal neurons and elicit monosynaptic glutamatergic excitatory postsynaptic potentials in output neurons of the optic tectum, reticulospinal neurons, and, as shown earlier, basal ganglia neurons. CONCLUSIONS: Our results demonstrate marked similarities in the efferent functional connectivity and control of motor behavior between the lamprey pallium and mammalian neocortex. Thus, the lamprey motor pallium/cortex represents an evolutionary blueprint of the corresponding mammalian system.
DOI:10.1016/j.cub.2017.09.034URLPMID:29056451 [本文引用: 1]
The basic architecture of the mammalian neocortex is remarkably similar across species. Pallial structures in the reptilian brain are considered amniote precursors of mammalian neocortex, whereas pallia of anamniotes (
DOI:10.1002/cne.21348URLPMID:17480011 [本文引用: 1]
The localization of gamma-aminobutyric acid (GABA) has been well described in most classes of vertebrates but not in adult lampreys. The question if the GABA distribution is similar throughout the vertebrate subphylum is therefore still to be addressed. We here investigate two lamprey species, the sea lamprey, Petromyzon marinus, and the river lamprey, Lampetra fluviatilis, and compare the GABA pattern with that of other vertebrates. The present immunohistochemical study provides an anatomical basis for the general distribution and precise localization of GABAergic neurons in the adult lamprey forebrain and brainstem. GABA-immunoreactive cells were organized in a virtually identical manner in the two species. They were found throughout the brain, with the following regions being of particular interest: the granular cell layer of the olfactory bulb, the nucleus of the anterior commissure, the septum, the lateral and medial pallia, the striatum, the nucleus of the postoptic commissure, the thalamus, the hypothalamus, and pretectal areas, the optic tectum, the torus semicircularis, the mesencephalic tegmentum, restricted regions of the rhombencephalic tegmentum, the octavolateral area, and the dorsal column nucleus. The GABA distribution found in cyclostomes is very similar to that of other classes of vertebrates, including mammals. Since the lamprey diverged from the main vertebrate line around 450 million years ago, this implies that already at that time the basic vertebrate plan for the GABA innervation in different parts of the brain had been developed.
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DOI:10.1038/nrn1519URLPMID:15378039 [本文引用: 1]
Mammals adapt to a rapidly changing world because of the sophisticated cognitive functions that are supported by the neocortex. The neocortex, which forms almost 80% of the human brain, seems to have arisen from repeated duplication of a stereotypical microcircuit template with subtle specializations for different brain regions and species. The quest to unravel the blueprint of this template started more than a century ago and has revealed an immensely intricate design. The largest obstacle is the daunting variety of inhibitory interneurons that are found in the circuit. This review focuses on the organizing principles that govern the diversity of inhibitory interneurons and their circuits.
DOI:10.1038/d41586-017-07550-9URLPMID:32080444 [本文引用: 1]
DOI:10.4103/1673-5374.257515URLPMID:31169176 [本文引用: 1]
DOI:10.1002/glia.22678URL [本文引用: 1]
In contrast to mammals, the spinal cord of lampreys spontaneously recovers from a complete spinal cord injury (SCI). Understanding the differences between lampreys and mammals in their response to SCI could provide valuable information to propose new therapies. Unique properties of the astrocytes of lampreys probably contribute to the success of spinal cord regeneration. The main aim of our study was to investigate, in the sea lamprey, the release of aminoacidergic neurotransmitters and the subsequent astrocyte uptake of these neurotransmitters during the first week following a complete SCI by detecting glutamate, GABA, glycine, Hu and cytokeratin immunoreactivities. This is the first time that aminoacidergic neurotransmitter release from neurons and the subsequent astrocytic response after SCI are analysed by immunocytochemistry in any vertebrate. Spinal injury caused the immediate loss of glutamate, GABA and glycine immunoreactivities in neurons close to the lesion site (except for the cerebrospinal fluid-contacting GABA cells). Only after SCI, astrocytes showed glutamate, GABA and glycine immunoreactivity. Treatment with an inhibitor of glutamate transporters (DL-TBOA) showed that neuronal glutamate was actively transported into astrocytes after SCI. Moreover, after SCI, a massive accumulation of inhibitory neurotransmitters around some reticulospinal axons was observed. Presence of GABA accumulation significantly correlated with a higher survival ability of these neurons. Our data show that, in contrast to mammals, astrocytes of lampreys have a high capacity to actively uptake glutamate after SCI. GABA may play a protective role that could explain the higher regenerative and survival ability of specific descending neurons of lampreys.
DOI:10.1038/s41598-017-18757-1URLPMID:29335507 [本文引用: 1]
In mammals, spinal cord injury (SCI) leads to dramatic losses in neurons and synaptic connections, and consequently function. Unlike mammals, lampreys are vertebrates that undergo spontaneous regeneration and achieve functional recovery after SCI. Therefore our goal was to determine the complete transcriptional responses that occur after SCI in lampreys and to identify deeply conserved pathways that promote regeneration. We performed RNA-Seq on lamprey spinal cord and brain throughout the course of functional recovery. We describe complex transcriptional responses in the injured spinal cord, and somewhat surprisingly, also in the brain. Transcriptional responses to SCI in lampreys included transcription factor networks that promote peripheral nerve regeneration in mammals such as Atf3 and Jun. Furthermore, a number of highly conserved axon guidance, extracellular matrix, and proliferation genes were also differentially expressed after SCI in lampreys. Strikingly, ~3% of differentially expressed transcripts belonged to the Wnt pathways. These included members of the Wnt and Frizzled gene families, and genes involved in downstream signaling. Pharmacological inhibition of Wnt signaling inhibited functional recovery, confirming a critical role for this pathway. These data indicate that molecular signals present in mammals are also involved in regeneration in lampreys, supporting translational relevance of the model.
DOI:10.1038/s41419-018-0704-9URLPMID:29950557 [本文引用: 2]
The poor regenerative capacity of descending neurons is one of the main causes of the lack of recovery after spinal cord injury (SCI). Thus, it is of crucial importance to find ways to promote axonal regeneration. In addition, the prevention of retrograde degeneration leading to the atrophy/death of descending neurons is an obvious prerequisite to activate axonal regeneration. Lampreys show an amazing regenerative capacity after SCI. Recent histological work in lampreys suggested that GABA, which is massively released after a SCI, could promote the survival of descending neurons. Here, we aimed to study if GABA, acting through GABAB receptors, promotes the survival and axonal regeneration of descending neurons of larval sea lampreys after a complete SCI. First, we used in situ hybridization to confirm that identifiable descending neurons of late-stage larvae express the gabab1 subunit of the GABAB receptor. We also observed an acute increase in the expression of this subunit in descending neurons after SCI, which further supported the possible role of GABA and GABAB receptors in promoting the survival and regeneration of these neurons. So, we performed gain and loss of function experiments to confirm this hypothesis. Treatments with GABA and baclofen (GABAB agonist) significantly reduced caspase activation in descending neurons 2 weeks after a complete SCI. Long-term treatments with GABOB (a GABA analogue) and baclofen significantly promoted axonal regeneration of descending neurons after SCI. These data indicate that GABAergic signalling through GABAB receptors promotes the survival and regeneration of descending neurons after SCI. Finally, we used morpholinos against the gabab1 subunit to knockdown the expression of the GABAB receptor in descending neurons. Long-term morpholino treatments caused a significant inhibition of axonal regeneration. This shows that endogenous GABA promotes axonal regeneration after a complete SCI in lampreys by activating GABAB receptors.
DOI:10.1089/neu.2019.6604URLPMID:31469029 [本文引用: 1]
Taurine is one of the most abundant free amino acids in the brain. It is well known that taurine protects the brain from further damage after a traumatic event. However, only a few ex vivo studies have looked at the possible role of taurine in the regulation of axon regeneration after injury. Here, we aimed to reveal the possible role for taurine in the modulation of axonal regeneration following a complete spinal cord injury (SCI) using lampreys as an animal model. The brainstem of lampreys contains several individually identifiable descending neurons that differ greatly in their capacity for axonal regeneration after SCI. This offers a convenient model to promote or inhibit axonal regrowth in the same in vivo preparation. First, we carried out high performance liquid chromatography experiments to measure taurine levels in the spinal cord following SCI. Our results revealed a statistically significant increase in taurine levels 4 weeks post-lesion, which suggested that taurine might have a positive effect on axonal regrowth. Based on these results, we decided to apply an acute taurine treatment at the site of injury to study its effect on axon regeneration. Results from these experiments show that an acute taurine treatment enhances axonal regeneration following SCI in lampreys. This offers a novel way to try to promote axon regeneration after nervous system injuries in mammalian models.
DOI:10.1007/BF01915363URLPMID:700037 [本文引用: 1]
Degeneration of the bile ducts and gallbladder occurs during metamorphosis of the lamprey. Morphological aspects of this process suggest a similarity to human biliary atresia.
DOI:10.1002/hep4.1461URLPMID:32025607 [本文引用: 1]
Biliary atresia (BA) is a rare neonatal disease with unknown causes. Approximately 10% of BA cases develop in utero with other congenital defects that span a large spectrum of disease variations, including degeneration of the gall bladder and bile duct as well as malformation of the liver, intestines, and kidneys. Similar developmental alterations are manifested in a unique animal model, the sea lamprey (Petromyzon marinus), in which BA occurs naturally during metamorphosis. With the likelihood of conserved developmental mechanisms underlying organogenesis and degeneration, lamprey developmental BA may be a useful model to infer mechanisms underlying human embryonic BA. We reasoned that hepatobiliary transcriptomes regulate the transition between landmark stages of BA. Therefore, we examined sea lamprey hepatobiliary transcriptomes at four stages (M0, metamorphic stage 0 or larval stage, no BA; M2, metamorphic stage 2, onset of BA; M5, metamorphic stage 5, BA, and heightened hepatocyte proliferation and reorganization; and JV, juvenile, completion of BA) using messenger RNA sequencing and Kyoto Encyclopedia of Genes and Genomes pathway analyses. We found gene-expression patterns associated with the transition between these stages. In particular, transforming growth factor beta (TGF-beta), hedgehog, phosphatidylinositol-4,5-bisphosphate 3-kinase-Akt, Wnt, and mitogen-activated protein kinase pathways were involved during biliary degeneration. Furthermore, disrupting the TGF-beta signaling pathway with antagonist or small interfering RNA treatments at the onset of BA delayed gall bladder and bile duct degeneration. Conclusion: Distinctive gene-expression patterns are associated with the degeneration of the biliary system during developmental BA. In addition, disrupting TGF-beta signaling pathway at the onset of BA delayed biliary degeneration.
DOI:10.1002/aja.1001560205URLPMID:506952 [本文引用: 1]
The ultrastructure of hepatocytes, bile canaliculi, and hepatic sinusoids of the larval lamprey, Petromyzon marinus, was examined using thin-sectioned and freeze-fractured tissues. The liver is a
DOI:10.1155/2015/832943URLPMID:26101777 [本文引用: 1]
Biliary atresia (BA) is a progressive, inflammatory, and fibrosclerosing cholangiopathy in infants that results in obstruction of both extrahepatic and intrahepatic bile ducts. It is the most common cause for pediatric liver transplantation. In contrast, the sea lamprey undergoes developmental BA with transient cholestasis and fibrosis during metamorphosis, but emerges as a fecund adult with steatohepatitis and fibrosis in the liver. In this paper, we present new histological evidence and compare the sea lamprey to existing animal models to highlight the advantages and possible limitations of using the sea lamprey to study the etiology and compensatory mechanisms of BA and other liver diseases. Understanding the signaling factors and genetic networks underlying lamprey BA can provide insights into BA etiology and possible targets to prevent biliary degeneration and to clear fibrosis. In addition, information from lamprey BA can be used to develop adjunct treatments for patients awaiting or receiving surgical treatments. Furthermore, the cholestatic adult lamprey has unique adaptive mechanisms that can be used to explore potential treatments for cholestasis and nonalcoholic steatohepatitis (NASH).
DOI:10.1016/S0009-9120(01)00215-6URL [本文引用: 1]
Abstract
Objectives: To determine what changes are occurring in patients with primary sclerosing cholangitis (PSC) by examining perisinusoidal macrophages (Kupffer cells) in liver biopsies; 2-to measure transforming growth factor beta (TGFβ) as a marker of fibrosis in these patients.Design and methods: Transmission electron microscopy and immunohistochemistry of 15 PSC, 26 primary biliary cirrhosis (PBC), 30 alcoholic liver disease (ALD) and 51 with normal histology was used. Five PSC, 30 ALD and 120 normal volunteers were sampled for serum levels of TGFβ.
Results: There was a three-fold increase in relative numbers of Kupffer cells in PSC compared to PBC and to patients whose livers had normal histology. In PSC there was an accumulation of perisinusoidal macrophages, which was not associated with focal necrosis or with cholestasis. The levels of TGFβ in PSC were 54 ± 2 in cirrhotic versus 34 ± 5 in non-cirrhotic patients (p < 0.005).
Conclusion: The persistent activation of these macrophages may lead to the chronic release of TGFβ and contribute to chronic inflammation, fibrosis and cirrhosis.
DOI:10.1194/jlr.R800057-JLR200URL [本文引用: 1]
DOI:10.1152/physrev.00015.2003URLPMID:14715917 [本文引用: 1]
The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogenesis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.
DOI:10.1515/hmbci-2014-0022URLPMID:25390014 [本文引用: 1]
The growing understanding of adipose tissue as an important endocrine organ with multiple metabolic functions has directed the attention to the (patho)physiology of distinct fat depots. Brown adipose tissue (BAT), in contrast to bona fide white fat, can dissipate significant amounts of chemical energy through uncoupled respiration and heat production (thermogenesis). This process is mediated by the major thermogenic factor uncoupling protein-1 and can be activated by certain stimuli, such as cold exposure, adrenergic compounds or genetic alterations. White adipose tissue (WAT) depots, however, also possess the capacity to acquire brown fat characteristics in response to thermogenic stimuli. The induction of a BAT-like cellular and molecular program in WAT has recently been termed
DOI:10.1242/jeb.085746URL [本文引用: 1]
DOI:10.1111/j.1432-1033.1978.tb12045.xURLPMID:624284 [本文引用: 1]
Brown-adipose-tissue mitochondria possess an energy-dissipating ion uniport which is inhibited by purine nucleotides. The regulatory nucleotides bind to a high-affinity site on the outer face of the inner membrane which is independent of the adenine nucleotide translocator. A direct correlation between affinity for the regulatory site and ability to inhibit the ion uniport is demonstrated for a number of nucleotide analogues. 8-Azido-adenosine 5'-triphosphate, a photoaffinity label, also competes with GDP for the binding site and induces respiratory control. 8-Azido-adenosine [gamma-32P]triphosphate was prepared and covalently bound to hamster brown-adipose-tissue mitochondria by near-ultraviolet irradiation. Two major radioactive bands were identified of apparent molecular weight 30000 and 32000, representing 6% and 10% of the inner membrane protein respectively. Selective labelling enabled the 30000-Mr protein to be identified as the carboxyatractylate binding component of the adenine-nucleotide translocator and the 32000-Mr protein to be identified as the regulatory site of the energy-dissipating ion uniport. The levels of the 32000-Mr protein in the inner membrane of guinea-pig brown-adipose-tissue mitochondria correlate with the degree of thermogenic adaptation of the animal.
DOI:10.1172/JCI67803URL [本文引用: 1]
Brown adipose tissue (BAT) burns fat to produce heat when the body is exposed to cold and plays a role in energy metabolism. Using fluorodeoxyglucose-positron emission tomography and computed tomography, we previously reported that BAT decreases with age and thereby accelerates age-related accumulation of body fat in humans. Thus, the recruitment of BAT may be effective for body fat reduction. In this study, we examined the effects of repeated stimulation by cold and capsinoids (nonpungent capsaicin analogs) in healthy human subjects with low BAT activity. Acute cold exposure at 19 degrees C for 2 hours increased energy expenditure (EE). Cold-induced increments of BE (CIT) strongly correlated with BAT activity independently of age and fat-free mass. Daily 2-hour cold exposure at 17 degrees C for 6 weeks resulted in a parallel increase in BAT activity and CIT and a concomitant decrease in body fat mass. Changes in BAT activity and body fat mass were negatively correlated. Similarly, daily ingestion of capsinoids for 6 weeks increased CIT. These results demonstrate that human BAT can be recruited even in individuals with decreased BAT activity, thereby contributing to body fat reduction.
DOI:10.1016/j.tem.2013.12.004URLPMID:24389130 [本文引用: 1]
Brown adipose tissue (BAT) dissipates energy as heat to maintain optimal thermogenesis and to contribute to energy expenditure in rodents and possibly humans. The energetic processes executed by BAT require a readily-available fuel supply, which includes glucose and fatty acids (FAs). FAs become available by cellular uptake, de novo lipogenesis, and multilocular lipid droplets in brown adipocytes. BAT also possesses a great capacity for glucose uptake and metabolism, and an ability to regulate insulin sensitivity. These properties make BAT an appealing target for the treatment of obesity, diabetes, and other metabolic disorders. Recent research has provided a better understanding of the processes of fuel utilization carried out by brown adipocytes, which is the focus of the current review.
DOI:10.1056/NEJMoa0808718URLPMID:19357405 [本文引用: 1]
BACKGROUND: Studies in animals indicate that brown adipose tissue is important in the regulation of body weight, and it is possible that individual variation in adaptive thermogenesis can be attributed to variations in the amount or activity of brown adipose tissue. Until recently, the presence of brown adipose tissue was thought to be relevant only in small mammals and infants, with negligible physiologic relevance in adult humans. We performed a systematic examination of the presence, distribution, and activity of brown adipose tissue in lean and obese men during exposure to cold temperature. Brown-adipose-tissue activity was studied in relation to body composition and energy metabolism. METHODS: We studied 24 healthy men--10 who were lean (body-mass index [BMI] [the weight in kilograms divided by the square of the height in meters], < 25) and 14 who were overweight or obese (BMI, > or = 25)--under thermoneutral conditions (22 degrees C) and during mild cold exposure (16 degrees C). Putative brown-adipose-tissue activity was determined with the use of integrated (18)F-fluorodeoxyglucose positron-emission tomography and computed tomography. Body composition and energy expenditure were measured with the use of dual-energy x-ray absorptiometry and indirect calorimetry. RESULTS: Brown-adipose-tissue activity was observed in 23 of the 24 subjects (96%) during cold exposure but not under thermoneutral conditions. The activity was significantly lower in the overweight or obese subjects than in the lean subjects (P=0.007). BMI and percentage of body fat both had significant negative correlations with brown adipose tissue, whereas resting metabolic rate had a significant positive correlation. CONCLUSIONS: The percentage of young men with brown adipose tissue is high, but its activity is reduced in men who are overweight or obese. Brown adipose tissue may be metabolically important in men, and the fact that it is reduced yet present in most overweight or obese subjects may make it a target for the treatment of obesity.
DOI:10.1016/j.cmet.2011.07.015URL [本文引用: 1]
Progress in preventing atherosclerotic coronary artery disease (CAD) has been stalled by the epidemic of type 2 diabetes. Further advances in this area demand a thorough understanding of how two major features of type 2 diabetes, insulin resistance and hyperglycemia, impact atherosclerosis. Insulin resistance is associated with systemic CAD risk factors, but increasing evidence suggests that defective insulin signaling in atherosclerotic lesional cells also plays an important role. The role of hyperglycemia in CAD associated with type 2 diabetes is less clear. Understanding the mechanisms whereby type 2 diabetes exacerbates CAD offers hope for new therapeutic strategies to prevent and treat atherosclerotic vascular disease.
DOI:10.1111/obr.12520URLPMID:28187240 [本文引用: 1]
Obesity is the result of energy intake chronically exceeding energy expenditure. Classical treatments against obesity do not provide a satisfactory long-term outcome for the majority of patients. After the demonstration of functional brown adipose tissue in human adults, great effort is being devoted to develop therapies based on the adipose tissue itself, through the conversion of fat-accumulating white adipose tissue into energy-dissipating brown adipose tissue. Anti-obesity treatments that exploit endogenous, pharmacological and nutritional factors to drive such conversion are especially in demand. In the present review, we summarize the current knowledge about the various molecules that can be applied in promoting white-to-brown adipose tissue conversion and energy expenditure and the cellular mechanisms involved.
DOI:10.1038/31927URLPMID:9582070 [本文引用: 1]
A timescale is necessary for estimating rates of molecular and morphological change in organisms and for interpreting patterns of macroevolution and biogeography. Traditionally, these times have been obtained from the fossil record, where the earliest representatives of two lineages establish a minimum time of divergence of these lineages. The clock-like accumulation of sequence differences in some genes provides an alternative method by which the mean divergence time can be estimated. Estimates from single genes may have large statistical errors, but multiple genes can be studied to obtain a more reliable estimate of divergence time. However, until recently, the number of genes available for estimation of divergence time has been limited. Here we present divergence-time estimates for mammalian orders and major lineages of vertebrates, from an analysis of 658 nuclear genes. The molecular times agree with most early (Palaeozoic) and late (Cenozoic) fossil-based times, but indicate major gaps in the Mesozoic fossil record. At least five lineages of placental mammals arose more than 100 million years ago, and most of the modern orders seem to have diversified before the Cretaceous/Tertiary extinction of the dinosaurs.
