初級纖毛與Wnt信號通路相關性研究進展

張蔓麗，盧彥平，李亞里

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初級纖毛與Wnt信號通路相關性研究進展

張蔓麗，盧彥平，李亞里

中國人民解放軍總醫(yī)院婦產科，北京 100853

初級纖毛是一類以微管為基礎結構的細胞器，其來源于細胞的母中心粒，錨定在細胞膜并如“天線”般突出細胞表面。作為細胞感受器，初級纖毛從環(huán)境中接受各種信號，傳導至細胞內引起細胞反應。近期的研究表明，初級纖毛對與胚胎發(fā)育密切相關的Wnt信號通路的傳導起重要作用。纖毛的損害可造成Wnt信號通路的異常，并引起胚胎中多類臟器一系列的病理改變，導致初級纖毛相關疾病的發(fā)生。文章主要闡述了初級纖毛與Wnt/β-catenin、Wnt/PCP通路及初級纖毛相關疾病之間的關系，并對初級纖毛相關疾病的治療進行了初步探討。對初級纖毛與Wnt信號通路關系的深入研究將有助于人們對該類疾病的進一步診斷和治療。

初級纖毛；Wnt信號通路；初級纖毛相關疾病

100多年以來，細胞表面微小的纖毛曾被認為是無用退化的細胞器。然而隨著對纖毛超微結構和功能的認識，人們發(fā)現纖毛借助信號通路在人類的胚胎發(fā)育、疾病發(fā)生中發(fā)揮著舉足輕重的作用。Wnt信號通路是參與胚胎及器官發(fā)育的主要信號傳導途徑之一。纖毛可以通過對Wnt信號通路的調控發(fā)揮“小而強大”的作用，纖毛結構與Wnt信號通路的損害與纖毛相關疾病的發(fā)生相關。本文對纖毛、初級纖毛相關疾病及Wnt信號通路相關領域的研究進展進行了綜述。

1 纖毛的結構和功能

1.1 纖毛的分類與結構

纖毛是一種突出于細胞表面的特殊結構。脊椎動物成體中幾乎所有類型的細胞表面都具有纖毛[1]，纖毛也廣泛存在于各種處于發(fā)育階段的動物胚胎細胞以及體外培養(yǎng)的哺乳動物細胞中[2~4]。根據其結構和運動能力，纖毛分為運動纖毛及初級纖毛(即靜纖毛、不動纖毛)。目前，人體中共發(fā)現4類纖毛結構[5]。典型的運動纖毛由9組外周微管和1對中央微管構成(即9+2結構)。每個細胞可有多根運動纖毛，執(zhí)行細胞的運動功能，如黏液的運輸、精子細胞和卵細胞的移動等。初級纖毛主要為感覺纖毛，分布于視覺、嗅覺和聽覺細胞等。典型的初級纖毛由 9 對外周微管構成，無中央微管(即9+0結構)，每個細胞僅有一根初級纖毛[5~8]。以(9+0)初級纖毛為例，其結構從頂端向下分為：毛頂部、纖毛膜、軸絲部、轉化區(qū)和基體?；w向下以根毛延伸至細胞內部，有些位于高爾基體附近，起錨定作用，向上以基足包埋微管末端，起固定微管作用[7~9]。

1.2 纖毛的組裝與解聚

纖毛的形成始于基體。首先，母中心粒(成熟中心粒)轉化為基體，然后自基體組裝軸絲。根據細胞類型不同，纖毛組裝方式分為2種：在上皮細胞(如肺、腎臟)，基體先定位并錨定于細胞膜，從膜頂端開始組裝纖毛，延伸向細胞外；而在間充質細胞、成纖維細胞及神經元前體細胞中，高爾基體來源的囊泡先接觸母中心粒遠端附屬，隨后形成囊泡與之不斷融合形成纖毛膜，同時伴隨軸絲產生[7]。這一組裝過程開始于細胞周期G1期[9]。

纖毛本身缺乏其組裝、維持和分解所需蛋白的合成系統，故需要通過鞭毛內運輸系統從細胞內轉運所需物質，這是一個由鞭毛內運輸蛋白(Intrafla-gellar transport, IFT)介導的沿微管運行的雙向物質運輸系統。一方面IFT顆粒復合體-B(包括IFT-88、IFT-172等13個IFT蛋白)負責蛋白從細胞內至纖毛的順向運輸，而另一方面IFT-A(有6個IFT蛋白)則負責纖毛至細胞內的逆向運輸，即IFT-B復合體攜帶軸絲生長物質至纖毛頂端，IFT-A復合體將傳回物質及信號傳導成分轉至細胞內。驅動蛋白-Ⅱ家族(脊椎動物中為驅動蛋白家族蛋白3a(Kinesin family member 3a, Kif3a)/Kif3b/非動力亞單位KAP 復合體)和動力馬達蛋白作為分子動力參與這一過程，兩者分別介導IFT-B和IFT-A?；w和纖毛頂端也參與協調IFT 顆粒運輸過程，并控制軸絲的裝配、延長和解聚，從而調節(jié)纖毛的生長、穩(wěn)定及重吸收的過程。阻斷驅動蛋白Ⅱ或IFT中任何一個蛋白，會導致初級纖毛異常，出現多種發(fā)育和細胞信號缺陷，形成纖毛相關疾病[10~12]。

纖毛的分解則可能由一個定位于中心體的蛋白激酶——極光激酶A(Aurora A)發(fā)起。研究表明，組蛋白去乙?；?(Histone deacetylase, HDAC6)、Pitchfork蛋白 (Pifo)、驅動蛋白Kinesin-13、驅動蛋白家族成員Kif19A等均參與了纖毛分解過程，具體機制仍需進一步研究[7]。

1.3 纖毛的功能

纖毛曾被認為是哺乳動物進化過程中退化的細胞器。然而研究顯示，初級纖毛膜表面存在大量的纖毛特有受體及離子通道，如血小板源性的生長因子受體(Platelet derived growth factor receptor alpha, PDGFR-α)、生長抑素受體、5-羥色胺受體、多囊蛋白(Polycystin, PC)PC1和PC2及Hedgehog(Hh)、Wnt信號通路的組成部件等[13]，因此初級纖毛主要被認為是一種感受器[14]，感知光、機械能、滲透壓、溫度及激素等[15]。脊椎動物的嗅覺及光感受器均由初級纖毛生成。在腎臟、肝臟、胰腺、輸卵管等細胞中，初級纖毛如同“天線”傳導外界環(huán)境信號至細胞內，調節(jié)胚胎發(fā)育及組織的內穩(wěn)態(tài)[13, 14]。一系列的證據表明，初級纖毛也參與了細胞周期的調控，因此缺陷的初級纖毛可能與癌癥相關[16,17]。此外，初級纖毛還參與指導細胞增殖分化、細胞極性及神經生長、神經管發(fā)育、骨骼發(fā)育、胚胎干細胞發(fā)育等[15, 18~20]。由于這些作用的發(fā)生均依賴纖毛上信號傳導通路的存在，說明初級纖毛在信號傳導(如Hh、Wnt信號通路及鈣信號、PDGFRα信號傳導等)方面發(fā)揮著關鍵作用，從而參與人體眾多組織和器官的發(fā)育及正常生理活動。

2 初級纖毛與Wnt信號通路關系

目前，研究初級纖毛的功能主要集中在2條通路，即Hh和Wnt信號通路。對Hh信號通路的研究較為廣泛，其在初級纖毛信號傳導具有重要作用。但對于Wnt通路的作用尚有爭議。Wnt信號通路至少有3種，包括經典的Wnt/β-catenin 通路、Wnt /PCP通路(Planar cell polarity pathway)、Wnt/鈣離子(Wnt /Ca2+)通路，其中經典的Wnt/β-catenin和Wnt/PCP通路與初級纖毛的關系尤為重要。研究表明，經典的Wnt/β-catenin 信號通路與初級纖毛有密切聯系。(1)Wnt/β-catenin 信號通路中的重要成分糖原合成酶激酶-3β(Glycogen synthase kinase-3β, GSK-3β)和結腸腺瘤樣息肉病蛋白(Adenomatous polyposis coli, APC)都定位于初級纖毛上[21,22]。對衣藻()鞭毛的研究指出，GSK-3β可使微管相關蛋白tau磷酸化，從而降低微管形成的穩(wěn)定性，同時也影響纖毛的順向運輸。抑制GSK3會導致萊茵衣藻()鞭毛變長，從而提示GSK3對鞭毛的組裝和維持有一定的調節(jié)作用[21]；(2)纖毛可以負調控Wnt/β-catenin 信號通路，因此提示纖毛的異常會導致Wnt/β-catenin 通路的激活。多種動物、細胞模型驗證了這一點。如在Orpk小鼠(多囊腎小鼠模型)胰腺擴張的腺管及囊腫中，細胞漿的β-catenin水平升高，T細胞因子/淋巴增強因子(T-cell factor/lymphoid enhancing factor, TCF/LEF)表達增 加[23]，而纖毛數量和長度都明顯下降，這表明在胰腺中初級纖毛參與了Wnt信號通路的調節(jié)；將小鼠基因突變后，其關節(jié)生長板的軟骨細胞不僅出現初級纖毛減少，細胞核內的β-catenin 在轉錄水平明顯升高[24]。Kevin等[22]在破壞了纖毛形成的小鼠胚胎、原代成纖維細胞和胚胎干細胞中均檢測到Wnt通路的上調。他們同時敲除了HEK293細胞中與纖毛組裝相關的驅動蛋白Kif3a，發(fā)現在沒有外源Wnt刺激因子情況下HEK293細胞中Wnt通路處于激活狀態(tài)；(3)研究發(fā)現初級纖毛能夠使β-catenin定位于基體中，并限制其入核過程，從而抑制Wnt/β-catenin 信號通路[25]。還有報道稱利用shRNA技術敲除HEK293T細胞的巴-比二氏綜合征(Bardet-Biedl syndrome, BBS)蛋白4或6基因，會增強Wnt3a刺激下TCF/LEF1活性[26]。然而也存在爭論：有學者發(fā)現在缺失纖毛的動物模型中Wnt/ β-catenin信號通路不受影響[27, 28]。經典Wnt/β-ca-tenin通路與初級纖毛之間的關系究竟如何，值得進一步探究。

與經典Wnt/β-catenin 信號通路相反，PCP通路在纖毛相關疾病中被認為是下調的。PCP通路相關基因有助于細胞表面肌動蛋白actin的富集，后者為中心體/基體的細胞膜錨定功能所必需。在非洲爪蟾()模型中，破壞PCP相關基因和可導致肌動蛋白和纖毛形成能力的喪失[29]。研究發(fā)現，PCP通路相關蛋白Inversin(即NPHP2)、Diversin、Vangle-2、Fat4也位于初級纖毛或基體 上[30~33]。Simons等[34]、Schwarz-Romond等[35]認為Inversin (NPHP2)和Diversin均可擔當經典和非經典Wnt通路之間分子轉換開關的角色，前者通過靶向性降低細胞質中的蓬亂蛋白(Dishevelled, Dvl/Dsh)，后者通過刺激JNK信號通路，兩者均可抑制經典Wnt/β-catenin 信號通路。Inversin是PCP通路的關鍵調控蛋白，Inversin基因突變將導致腎囊腫的形成，與纖毛缺失造成的表型類似[36]。而Inversin基因敲除的斑馬魚()會形成腎囊腫，在給予補充Diversin后可以對抗這一現象[35]。在非洲爪蟾多纖毛皮膚細胞中過表達Diversin RNA 將會破壞纖毛基體極性；而敲除內源性Diversin的細胞中，基體的結構異常，極性破壞，細胞纖毛變短或喪失[33]。關于初級纖毛對Wnt信號通路各個分支如何作用？在信號通路中是對哪些關鍵調控蛋白產生影響？這些作用又是在細胞膜上、胞內、細胞核哪一部位發(fā)生的？Wnt/β-catenin 與PCP信號通路之間究竟如何關聯？這些疑問均未得到確切的釋疑，有必要對此進一步研究。

3 初級纖毛、纖毛相關疾病與Wnt信號通路

現已確認初級纖毛和Wnt信號通路成分缺失或異常與多種人類疾病有關。有學者將人體先天性基因突變造成初級纖毛結構及功能破壞導致的多種疾病，統稱為初級纖毛相關疾病(Ciliopathies)[37, 38]。這類疾病涉及人體多種器官，如腎臟、腦部、四肢、眼部、耳、肝臟、骨骼等，其表型包括多囊腎、肝膽疾病、多指/趾、胼胝體缺失、認知障礙、視網膜退化、后顱窩缺陷、骨骼異常、肥胖等[39]。

初級纖毛相關疾病包括：巴-比二氏綜合征 (Bardet-Biedl syndrome, BBS)，青少年型消耗性腎病 (Nephronophthisis,NPHP)，Senior-Lken 綜合征(SLNS)，Alstrm 綜合征 (ALMS)，麥克爾綜合征 (Meckel-Gruber syndrome, MKS)，Joubert綜合征 (JBTS)，1型口面指綜合征 (Oral-facial-digital syndrome, OFD1)，埃利偉氏綜合征 (Ellis-van Creveld syndrome, EVC)及先天性利伯氏黑矇(Leber congenital amaurosis, LCA)和多囊腎病(Polycystic kidney disease, PKD)等。隨著對初級纖毛的認識，這一疾病的種類還在不斷擴增。目前，本文作者統計出的與上述疾病相關基因達115種，這些基因的蛋白產物定位于纖毛上，與初級纖毛相關疾病及Wnt信號通路密切相關。比如：與多囊腎相關的基因蛋白產物PKD1和PKD2位于人和小鼠的腎臟初級纖毛上[40, 41]，而初級纖毛相關基因發(fā)生突變的小鼠身上纖毛功能異常，過度表達活性β-catenin，并出現多囊腎癥狀[42, 43]；Wnt/PCP通路改變與基因——、或突變造成的小鼠之間表型頗為相似[44]；與IFT及纖毛組裝相關基因變異的小鼠細胞纖毛變短，并出現一系列發(fā)育缺陷。變異的小鼠細胞核中探測到強烈的β-catenin信號，而Wnt通路的靶基因和表達顯著上調[45,24]；基因和基因分別編碼纖毛蛋白MKS1和meckelin (MKS3)，這兩個基因的突變可以導致纖毛及中心體缺陷，參與神經管等多器官發(fā)育障礙發(fā)生，從而導致MKS綜合征[46]，而在MKS3裸鼠模型腎臟組織中經典Wnt通路處于激活狀態(tài)[47]。

然而初級纖毛相關疾病錯綜復雜，各種疾病的基因、表型互相重疊、交織，同一基因不同位點突變可以出現不同疾病，而不同的疾病可以有多種表型重疊。比如基因突變可以導致MKS 或 JBTS[48]。MKS、BBS和NPHP都可以有腎臟、肝臟、多趾/指畸形等相同器官病理改變。這表明初級纖毛相關疾病是一類由潛在突變基因的類型、數量、位置而調控的疾病譜。由于基因改變誘發(fā)纖毛結構改變而造成初級纖毛相關疾病，或是初級纖毛僅依賴一條或幾條通路而發(fā)揮作用，似乎不足以完全解釋這種復雜性?；蛟S纖毛的缺陷只是細胞內各種機制網絡作用失調的表現之一[49]。另有研究顯示，纖毛Ift蛋白不僅定位于基體，還可以定位于高爾基體附屬器上[50]。這一現象擴大了人們對纖毛及纖毛相關疾病的認識，有助于對發(fā)病機理的深層次理解。

4 治療及展望

很多初級纖毛相關疾病具致死性，其表型在胚胎期就可以出現，輕度的如BBS或NPHP中的一些類型的孩子可以存活，但生活質量差，往往早夭。目前對初級纖毛相關疾病尚無可靠而確切的治療方法。

利用藥物抑制環(huán)磷酸腺苷(Cyclic adenosine monophosphate, cAMP)和哺乳動物雷帕霉素靶蛋白(Mammalian target of rapamycin, mTOR)來降低細胞增殖及細胞內液體分泌，延緩了PKD的進展[51, 52]。在敲除小鼠模型上使用丙戊酸、胍那芐和半胱天冬酶12抑制劑復合物可以維持其光感受能 力[53]。藥物治療的靶點多與信號通路相關，鑒于纖毛相關疾病與多種信號通路之間的密切關系，將來或可選擇影響信號通路的藥物來達到改善初級纖毛相關疾病癥狀的目的。

基因治療帶來了希望。目前主要是利用基因送遞去對抗因目的基因失效產生的初級纖毛相關疾病。第一例基因治療的活體案例是在ORPK小鼠上實施的。這種小鼠的基因變異造成鼻腔嗅覺感覺神經元的纖毛異常，因此嗅覺喪失。將構建有基因的腺病毒載體連續(xù)感染小鼠，發(fā)現其嗅覺部分恢復，從而證明了基因治療的可行性[54]。

然而藥物和基因治療仍處于探索階段，治療具有不確切性。考慮到初級纖毛相關疾病中不少病例屬于單基因病，因此利用植入前遺傳學診斷(Preimplantation genetic diagnosis, PGD)可規(guī)避具有致病基因的受精卵。本院曾收治一對連續(xù)4次妊娠Meckel綜合征胎兒的夫婦，發(fā)現了其致病基因的純合突變c.1645C>T，2012年3月通過PGD技術幫助這對夫婦順利產下了一健康男嬰，這是目前發(fā)表的第一篇關于Meckel綜合征的植入前基因診斷的報道[55]。

綜上所述，對纖毛功能、致病基因、相關信號通路的深入研究，將有助于對初級纖毛相關疾病的認識，以期在未來利用分子遺傳學診斷、基因治療及影響信號通路等各種手段防治纖毛相關疾病。

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(責任編委: 楊曉)

Correlation between primary cilium and Wnt signaling pathway

Manli Zhang, Yanping Lu, Yali Li

Primary cilium is a microtubule-based organelle,which develops from the mother centriole of the centrosome. It is an antenna-like structure that anchors at the cell membrance, protruding from the cell surface. Primary cilium acts as a sensory organelle that receives different kinds of signals from the environment and transmits signals to cells to elicit cellular responses. Recent studies have revealed that primary cilium play an important role in transmitting Wnt signaling, which is critical for embryonic development. Dysfunction of primary cilium deregulates Wnt signaling, causing a series of pathological changes in different organs of the embryo, resulting in ciliopathies. In this review, we summarize correlation among primary cilium,Wnt/β-catenin signaling,Wnt/PCP signaling and ciliopathies. Current therapies in ciliopathies are also discussed. Highlights on these researches will encourage the development of Wnt-associated diagnostic tools and therapy for ciliopathies.

primary cilium;Wnt signaling; ciliopathies

2014-07-28;

2014-12-05

解放軍總醫(yī)院科研扶持基金項目資助

張蔓麗，博士研究生，主治醫(yī)師，研究方向：遺傳疾病的分子診斷及產前診斷。E-mail:zhangmanli1982@126.com

盧彥平，博士，副教授，主任醫(yī)師，研究方向：遺傳疾病的分子診斷及產前診斷。E-mail: luyp301@163.com李亞里，教授，博士生導師，主任醫(yī)師，研究方向：產前診斷及子宮內膜異位癥發(fā)病機理。E-mail: li_yali@hotmail.com

10.16288/j.yczz.14-252

2015-1-5 10:51:23

http://www.cnki.net/kcms/detail/11.1913.R.20150105.1051.002.html