Wnt信號(hào)通路在神經(jīng)發(fā)生中的作用

張彬渝，余永莉

(遵義醫(yī)學(xué)院珠海校區(qū)人體解剖與組織胚胎教研室，廣東 珠海 519041)

Wnt信號(hào)通路在神經(jīng)發(fā)生中的作用

張彬渝，余永莉

(遵義醫(yī)學(xué)院珠海校區(qū)人體解剖與組織胚胎教研室，廣東 珠海 519041)

Wnt信號(hào)通路在哺乳動(dòng)物的生長(zhǎng)發(fā)育過(guò)程中調(diào)節(jié)細(xì)胞的增殖、分化、遷移和極化等過(guò)程。Wnt信號(hào)通路與神經(jīng)發(fā)生關(guān)系密切，大量的研究顯示，該通路突變或異?？僧a(chǎn)生諸多神經(jīng)系統(tǒng)疾病。Wnt信號(hào)通路的失調(diào)還與癌癥、神經(jīng)退行性疾病的發(fā)生密切相關(guān)。研究發(fā)現(xiàn)，成年哺乳動(dòng)物腦細(xì)胞受損后Wnt信號(hào)通路會(huì)被啟動(dòng)，從而促進(jìn)神經(jīng)干細(xì)胞的再生。本文從Wnt信號(hào)通路出發(fā)，通過(guò)分析Wnt信號(hào)通路在神經(jīng)發(fā)生中的作用，有助于深入理解神經(jīng)發(fā)育過(guò)程中Wnt信號(hào)通路的作用機(jī)制。

Wnt信號(hào)通路；神經(jīng)發(fā)生；癌癥；神經(jīng)系統(tǒng)疾病

Wnt信號(hào)通路是在通過(guò)對(duì)致癌逆轉(zhuǎn)錄病毒的研究中被發(fā)現(xiàn)的。1982年Nusse等發(fā)現(xiàn)并報(bào)道了Wnt基因?qū)儆谠┗颍Q之為int-1基因[1]。隨后發(fā)現(xiàn)與int-1基因合稱為wnt基因的同源基因wingless基因[2]。Wnt信號(hào)通路編碼的蛋白為分泌型糖蛋白，這些糖蛋白在進(jìn)化上保持高度保守，通過(guò)自分泌或旁分泌等分泌方式與細(xì)胞膜上的受體結(jié)合從而發(fā)揮作用[3]。它們?cè)诓溉閯?dòng)物不同發(fā)育階段的功能也是不同的。在神經(jīng)系統(tǒng)中，Wnt信號(hào)通路在神經(jīng)前體細(xì)胞增殖、分化以及決定細(xì)胞命運(yùn)的調(diào)控中扮演了重要角色[4]。同時(shí)還發(fā)現(xiàn)Wnt信號(hào)通路的異?；罨瘜?huì)導(dǎo)致神經(jīng)系統(tǒng)疾病的發(fā)生。本文就Wnt信號(hào)通路在神經(jīng)發(fā)生中的作用做一綜述。

1 Wnt信號(hào)通路

Wnt蛋白啟動(dòng)Wnt信號(hào)通路。研究發(fā)現(xiàn)Wnt信號(hào)通路由β連環(huán)蛋白、跨膜受體家族(Frizzled)、散亂蛋白(Dsh)、細(xì)胞外因子(Wnt)、共受體低密度脂蛋白相關(guān)蛋白5/6、結(jié)腸腺腫樣息肉病基因產(chǎn)物(APC)、糖原合成激酶-3β(GSK-3β)、轉(zhuǎn)錄因子TCF/LEF家族、軸蛋白(Axin)等幾種蛋白組成[5]。研究發(fā)現(xiàn)，Wnt信號(hào)通路可分為經(jīng)典的Wnt/β-catenin通路和非經(jīng)典的Wnt/ β-catenin通路[6]。

1.1 經(jīng)典的Wnt/β-catenin通路 Wnt信號(hào)通路中研究最為深入及廣泛的是經(jīng)典的Wnt/β-catenin通路，對(duì)細(xì)胞的增殖、分化、遷移、極性化和凋亡等過(guò)程進(jìn)行調(diào)節(jié)。其中β-catenin蛋白是經(jīng)典的Wnt信號(hào)通路的核心分子，同時(shí)也是其重要的調(diào)控位點(diǎn)，它在細(xì)胞內(nèi)的數(shù)量和狀態(tài)對(duì)該通路有決定性影響[7]。

2.2 非經(jīng)典的wnt/β-catenin通路 非經(jīng)典的Wnt/β-catenin通路是由其他一些離子或蛋白參與的，而無(wú)β-catenin蛋白的參與[8]。依據(jù)β-catenin蛋白所激活的各級(jí)信號(hào)分子可分為Wnt/Ca2+通路和Wnt/pcp通路。Wnt/Ca2+通路作為Wnt信號(hào)通路的一個(gè)分支，能促進(jìn)細(xì)胞內(nèi)Ca2+的釋放和對(duì)Ca2+依賴性的蛋白激酶II (CaM kinase II)及PKC(protein kinase C)的激活等都是Wnt/Ca2+通路的特征[9]，Wnt/Ca2+通路能抑制經(jīng)典的Wnt信號(hào)通路。散亂蛋白下游區(qū)、小G蛋白(Rho和Rac)等被此通路激活，進(jìn)而激活末端激酶(JNK)來(lái)發(fā)揮作用，參與對(duì)細(xì)胞骨架分布不對(duì)稱的調(diào)節(jié)及細(xì)胞極性的建立，重排細(xì)胞骨架和上皮細(xì)胞的協(xié)同極化[10]。

2 Wnt信號(hào)通路在神經(jīng)發(fā)生中的作用

早前研究認(rèn)為，只有動(dòng)物胚胎期或出生后的發(fā)育早期才存在神經(jīng)發(fā)生。然而，近來(lái)發(fā)現(xiàn)，動(dòng)物從胚胎到成體乃至整個(gè)生命過(guò)程中都有神經(jīng)發(fā)生[6]。研究顯示哺乳動(dòng)物胚胎期、成年期的細(xì)胞增殖、分化、極性、遷移和凋亡與Wnt信號(hào)通路息息相關(guān)，并且神經(jīng)系統(tǒng)的發(fā)育也離不開Wnt信號(hào)通路[11]。

2.1 Wnt信號(hào)通路在胚胎期神經(jīng)發(fā)生中的作用 Wnt基因幾乎參與了胚胎發(fā)育的全部過(guò)程，如胚胎期的分化、發(fā)育的正常軸向，決定細(xì)胞極性，在生長(zhǎng)發(fā)育的信息傳遞中起到至關(guān)重要的作用[12]。若該通路失調(diào)將會(huì)導(dǎo)致胚胎發(fā)育缺陷或夭折[13]。研究發(fā)現(xiàn)，小鼠Wnt1與神經(jīng)系統(tǒng)發(fā)育有關(guān)，若該基因異常會(huì)導(dǎo)致中腦和小腦的缺失，Wnt7與肢體發(fā)育有關(guān)，Wnt7突變會(huì)使整個(gè)前肢缺陷。Wnt基因在胚胎期神經(jīng)發(fā)育的各時(shí)段和空間上均有特征性的表達(dá)，例如，小鼠胚胎于9.5～12.5 d時(shí)，在端腦及脊髓中有Wnt-7b表達(dá)；而Wnt-3a的表達(dá)存在于端腦到脊髓的神經(jīng)管背方；Wnt-3和Wnt-7a的表達(dá)分別存在于間腦到脊髓神經(jīng)管的背、腹方；間腦、中腦交界區(qū)域及脊髓上Wnt-1特異表達(dá)[14]。經(jīng)典的Wnt信號(hào)通路參與哺乳動(dòng)物耳部的形成，有研究表明，Wnt信號(hào)的受體分布在耳杯背內(nèi)側(cè)部分，它不僅有助于衍生背面的內(nèi)耳結(jié)構(gòu)，還能衍生腹面的內(nèi)耳結(jié)構(gòu)，包括耳蝸、耳蝸前庭神經(jīng)、球囊[15]。以上研究顯示在小鼠早期神經(jīng)系統(tǒng)的發(fā)育過(guò)程有Wnt基因的參與。Gulacsi等[16]發(fā)現(xiàn)經(jīng)典的Wnt信號(hào)通路與胚胎時(shí)期哺乳動(dòng)物的神經(jīng)發(fā)生緊密聯(lián)系，它參與了神經(jīng)干細(xì)胞的增殖與分化、皮層模式建立、軸突形成等過(guò)程。此外，在胚胎發(fā)育過(guò)程中，哺乳動(dòng)物皮質(zhì)中神經(jīng)發(fā)生的啟動(dòng)和海馬中的細(xì)胞類型由Wnt信號(hào)通路的動(dòng)態(tài)變化控制著[17]。在爪蟾早期胚胎中幾乎每個(gè)細(xì)胞中都有Wnt基因的表達(dá)，受精后，母源的Wnt/ β-catenin信號(hào)被激活，誘導(dǎo)形成組織中心并決定胚胎的背腹軸向[18]。在原腸胚中，Wnt/β-catenin信號(hào)參與頭尾軸向細(xì)胞分化[19]。在小鼠胚胎中，若將β-catenin敲除，則會(huì)導(dǎo)致胚胎初級(jí)體軸的發(fā)育失敗[20]。有研究顯示，β-catenin信號(hào)能控制細(xì)胞的增殖與分化和神經(jīng)前體細(xì)胞的生長(zhǎng)[21-23]。在胚胎中期，Wnt信號(hào)活動(dòng)增強(qiáng)，到后期逐漸減弱。研究表明皮層中的齒狀回和海馬的結(jié)構(gòu)由Wnt信號(hào)梯度決定；反之，若異常的Wnt信號(hào)被激活，梯度被破壞，則新皮層的正常層狀結(jié)構(gòu)將會(huì)被損害。小鼠的Wnt1基因被敲除，中后腦形成嚴(yán)重的缺陷[24]。研究胚胎干細(xì)胞時(shí)，Kielman等[25]用多種方式致使APC基因發(fā)生突變，發(fā)現(xiàn)可使胚胎干細(xì)胞維持增殖而抑制其向三胚層組織分化。這主要是通過(guò)提高胞內(nèi)β-catenin的水平實(shí)現(xiàn)的。Lobjois等[26]研究運(yùn)動(dòng)神經(jīng)元祖細(xì)胞時(shí)發(fā)現(xiàn)，神經(jīng)發(fā)生與神經(jīng)祖細(xì)胞的位置、受激發(fā)的時(shí)間相關(guān)。同時(shí)還發(fā)現(xiàn)影響神經(jīng)發(fā)生的唯一因素不單只對(duì)細(xì)胞周期進(jìn)行調(diào)控，還有多種因素能影響神經(jīng)前體細(xì)胞的增殖、分化。最近Willert等[27]發(fā)現(xiàn)將Wnt3a蛋白純化后，骨髓干細(xì)胞通過(guò)體外培養(yǎng)能大量增殖并顯示β-catenin高表達(dá)；反之，干細(xì)胞的增殖會(huì)因Wnt信號(hào)途徑的阻斷則受阻。結(jié)果表明，若要使干細(xì)胞維持原始增殖狀態(tài)，則需要對(duì)Wnt/ β-catenin途徑進(jìn)行調(diào)控。

2.2 Wnt信號(hào)通路在成年動(dòng)物神經(jīng)發(fā)生中的作用 Wnt信號(hào)通路對(duì)于成年動(dòng)物的神經(jīng)發(fā)生也至關(guān)重要，它成為在動(dòng)物成年期調(diào)節(jié)神經(jīng)發(fā)生的關(guān)鍵通路。成年哺乳動(dòng)物神經(jīng)發(fā)生存在于海馬齒狀回的顆粒下層(SGZ)和腦室下區(qū)的側(cè)腦室外側(cè)壁(SVZ)，它在干細(xì)胞維持、神經(jīng)元成熟、軸突重塑、成人組織穩(wěn)態(tài)方面都有重要作用[28]。研究表明，Wnt信號(hào)的信號(hào)分子表達(dá)于成年齒狀回，其表達(dá)是隨神經(jīng)發(fā)生的變化進(jìn)行調(diào)節(jié)的，表明成年海馬神經(jīng)發(fā)生主要受Wnt信號(hào)調(diào)節(jié)。成年海馬星形膠質(zhì)細(xì)胞表達(dá)Wnt3。Wnt信號(hào)的衍生物是星形膠質(zhì)細(xì)胞在孤立的層次分析法中刺激Wnt/ β-Catenin信號(hào)以及誘導(dǎo)這些祖細(xì)胞向神經(jīng)元方向分化時(shí)產(chǎn)生的[29]。近來(lái)研究顯示，在DG肺門細(xì)胞核星形膠質(zhì)細(xì)胞中Wnt3高表達(dá)，并且GSK3β、β-Catenin信號(hào)在成年SGZ和齒狀回顆粒層細(xì)胞中十分活躍[30]。有研究表明，Wnt信號(hào)能誘導(dǎo)神經(jīng)元分化，并且能為缺血性損傷后的神經(jīng)元提供合適的存活環(huán)境[31]。Davis等[32]發(fā)現(xiàn)，小鼠海馬表達(dá)Wnt5a、Wnt7a于出生后7 d內(nèi)，其中Wnt7 b高表達(dá)；出生至14 d時(shí)Wnt7 b的表達(dá)顯著下降。研究同樣表明，星形膠質(zhì)細(xì)胞源性的Wnt信號(hào)在成年海馬干細(xì)胞中通過(guò)β-Catenin信號(hào)通路協(xié)調(diào)神經(jīng)母細(xì)胞增殖和神經(jīng)元分化。Mao等[33]研究發(fā)現(xiàn)，激活Wnt/β-Catenin信號(hào)通路能促進(jìn)成年神經(jīng)干細(xì)胞的增殖而非分化。此外，核孤兒受體TIX在成年神經(jīng)干細(xì)胞的增殖中顯示重要作用[34]，它直接誘導(dǎo)Wnt7a的轉(zhuǎn)錄。同時(shí)成年神經(jīng)干細(xì)胞通過(guò)經(jīng)典的Wnt信號(hào)通路在成年大腦的神經(jīng)源性區(qū)域促進(jìn)增殖和自我更新[35]。雖然這些研究主要集中于Wnt信號(hào)在成年海馬神經(jīng)發(fā)生中的作用，但Wnt信號(hào)也顯示對(duì)成年SVZ神經(jīng)發(fā)生的調(diào)節(jié)。Wnt3a和Wnt5a的過(guò)度表達(dá)促進(jìn)成年SVZ神經(jīng)祖細(xì)胞在體外增殖和分化[36]。Wnt信號(hào)通路不僅參與形成神經(jīng)元連接，同時(shí)也對(duì)突觸的功能和可塑性進(jìn)行調(diào)節(jié)[37]。

3 Wnt信號(hào)通路與疾病

3.1 Wnt信號(hào)通路與癌癥 自從Wnt信號(hào)通路被發(fā)現(xiàn)以來(lái)，它已與癌癥相關(guān)聯(lián)。Wnt信號(hào)通路的異?；蛲蛔儗?huì)導(dǎo)致惡性腫瘤發(fā)生，如骨肉瘤、結(jié)腸癌、多發(fā)性骨髓瘤、乳腺癌和前列腺癌等[38]。經(jīng)典的Wnt信號(hào)通路參與良性和惡性乳腺腫瘤的發(fā)展，它的存在是通過(guò)提升β-catenin在細(xì)胞核或細(xì)胞質(zhì)中的水平來(lái)顯現(xiàn)的，它可以通過(guò)免疫組織化學(xué)染色和免疫印跡來(lái)檢測(cè)[39]。Wnt3、Wnt5、Wnt10b等陸續(xù)被證實(shí)能夠誘導(dǎo)產(chǎn)生腫瘤。Wnt信號(hào)通路與其他癌癥的發(fā)展也相關(guān)，例如β-catenin水平失調(diào)，將會(huì)導(dǎo)致直腸癌、結(jié)腸癌等疾病的發(fā)生[40]。編碼β-catenin蛋白的基因CTNNBI表達(dá)的改變，可以在乳房結(jié)、前列腺癌、黑色素瘤、肺癌和其他癌癥中進(jìn)行測(cè)量[41]。并且有報(bào)道，活躍的Wnt信號(hào)通路使肝癌患者的肝細(xì)胞胞漿內(nèi)堆積β-catenin，甚至積聚在肝癌細(xì)胞的胞核中，且明顯高于正常肝組織，提示了活躍的Wnt信號(hào)通路在肝癌的發(fā)展中起到一定作用[42]。

3.2 Wnt信號(hào)通路與神經(jīng)退行性疾病 在神經(jīng)退行性疾病中，經(jīng)典的Wnt信號(hào)通路異常將會(huì)使神經(jīng)元的增殖、分化受影響，同時(shí)會(huì)對(duì)神經(jīng)元產(chǎn)生毒性作用，導(dǎo)致神經(jīng)元功能受損。Wnt信號(hào)通路可能與神經(jīng)退行性疾病如阿爾茨海默癥等有關(guān)。過(guò)度磷酸化的微管相關(guān)蛋白tau蛋白和聚集的β淀粉樣蛋白會(huì)產(chǎn)生神經(jīng)毒性[43]，從而導(dǎo)致海馬神經(jīng)元的大量死亡。有證據(jù)表明，Wnt信號(hào)通路的激活能阻止β淀粉樣蛋白產(chǎn)生神經(jīng)毒性，從而增強(qiáng)其保護(hù)作用[44]，表明Wnt信號(hào)對(duì)阿爾茨海默癥中由β淀粉樣蛋白導(dǎo)致的神經(jīng)損害起重要作用[45]。用糖原合成酶激酶3β抑制劑鋰處理后可以預(yù)防tau的過(guò)度磷酸化[46]。

4 Wnt信號(hào)通路與神經(jīng)再生

神經(jīng)損傷后的治療、再生及功能恢復(fù)長(zhǎng)久以來(lái)成為醫(yī)學(xué)界的難題之一。研究發(fā)現(xiàn)，成年哺乳動(dòng)物受到損傷性刺激后Wnt信號(hào)通路會(huì)被啟動(dòng)，進(jìn)而促進(jìn)神經(jīng)干細(xì)胞再生。David等[47]研究發(fā)現(xiàn)，該通路能對(duì)脊髓神經(jīng)干細(xì)胞和前體細(xì)胞的增殖分化進(jìn)行調(diào)節(jié)。在治療神經(jīng)損傷等方面能發(fā)揮一定作用。一些調(diào)節(jié)因子通過(guò)對(duì)Wnt信號(hào)通路進(jìn)行調(diào)節(jié)來(lái)對(duì)神經(jīng)發(fā)生產(chǎn)生影響。如增加Wnt3a，sFRP3會(huì)減少，導(dǎo)致Wnt信號(hào)增加、細(xì)胞增殖，使神經(jīng)元復(fù)雜性增加[48]。Wnt7a會(huì)使細(xì)胞發(fā)展和生長(zhǎng)的進(jìn)程加快。抑制神經(jīng)膠質(zhì)的再生[49]。Suh等[50]研究發(fā)現(xiàn)，脊髓損傷后，移植分泌Wnt蛋白的成纖維細(xì)胞對(duì)促進(jìn)軸突再生和功能恢復(fù)十分明顯。還有研究發(fā)現(xiàn)，Wnt信號(hào)似乎能夠通過(guò)增加在紋狀體的神經(jīng)或神經(jīng)元來(lái)促進(jìn)缺血性損傷之后的功能恢復(fù)[51]。

5 小 結(jié)

Wnt信號(hào)通路作為調(diào)控細(xì)胞增殖、分化、遷移和極性化過(guò)程的復(fù)雜的開放通路，與神經(jīng)系統(tǒng)的發(fā)育緊密相關(guān)。胚胎期和成年期哺乳動(dòng)物的神經(jīng)發(fā)生均有Wnt信號(hào)通路的參與。異常的Wnt信號(hào)通路會(huì)導(dǎo)致許多腫瘤或中樞神經(jīng)系統(tǒng)疾病。研究發(fā)現(xiàn)，Wnt信號(hào)通路還能在大腦的可塑中起重要作用，能促進(jìn)神經(jīng)干細(xì)胞的再生，對(duì)治療神經(jīng)系統(tǒng)缺陷有一定作用。Wnt信號(hào)通路怎樣實(shí)現(xiàn)對(duì)神經(jīng)發(fā)生過(guò)程的調(diào)控是未來(lái)的研究熱點(diǎn)。

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Function of WNT signaling pathways in neurogenesis

ZHANG Bin-yu,YU Yong-li.Department of Human Anatomy and Histoembryology,Zhuhai Campus,Zunyi Medical College,Zhuhai 519041,Guangdong,CHINA

WNT(Wingless-type MMTV integration site family member)signaling pathways regulate cellular proliferation,differentiation,migration,and polarization during mammalian growth and development.WNT signaling pathways are closely related to neural genesis and many researches have shown that mutation and anomaly in WNT signaling pathways may lead to many neural-related diseases.Disorders in WNT Signaling Pathways are also closely connected to the genesis of cancer,diabetes,and neuro-degenerative diseases.Researchers have found that WNT signaling pathways will be activated after adult mammalian brain cells are damaged,which will stimulate the regeneration of neural stem cells.In this paper,we analyze the role of WNT signaling pathways in neurogenesis,which contribute to the understanding of the role of WNT signaling pathways in neural development process.

Wnt signaling;Neurogenesis;Cancer;Nervous system disease

R741.04

A

1003—6350（2017）05—0791—04

2016-06-13)

余永莉。E-mail：627639159@qq.com

10.3969/j.issn.1003-6350.2017.05.035