神經(jīng)元放射狀遷移分子的研究進(jìn)展

蔣華玉 綜述, 王永剛 審校

(1. 同濟(jì)大學(xué)附屬楊浦醫(yī)院神經(jīng)內(nèi)科,上海 200090； 2. 上海交通大學(xué)醫(yī)學(xué)院附屬仁濟(jì)醫(yī)院神經(jīng)內(nèi)科,上海 200127)

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·綜 述·

神經(jīng)元放射狀遷移分子的研究進(jìn)展

蔣華玉1綜述, 王永剛2審校

(1. 同濟(jì)大學(xué)附屬楊浦醫(yī)院神經(jīng)內(nèi)科,上海 200090； 2. 上海交通大學(xué)醫(yī)學(xué)院附屬仁濟(jì)醫(yī)院神經(jīng)內(nèi)科,上海 200127)

神經(jīng)元放射狀遷移是神經(jīng)元遷移的主要方式,其對大腦皮質(zhì)板層結(jié)構(gòu)的形成非常重要。隨著對皮層神經(jīng)元放射狀遷移研究的深入,越來越多的神經(jīng)元放射狀遷移相關(guān)分子得以發(fā)現(xiàn),使神經(jīng)元放射狀遷移這一復(fù)雜而精確過程的調(diào)控機(jī)制也越來越明朗。神經(jīng)元放射狀遷移分子主要分為兩類,一類是下調(diào)相關(guān)分子表達(dá)后抑制了放射狀遷移,另一類則下調(diào)相關(guān)分子表達(dá)后增強(qiáng)了放射狀遷移。本文對近年來新發(fā)現(xiàn)的神經(jīng)元放射狀遷移相關(guān)分子進(jìn)行綜述。

神經(jīng)元放射狀遷移； 抑制； 增強(qiáng)

在大腦發(fā)育過程中,功能神經(jīng)元間相互聯(lián)系的建立離不開神經(jīng)元正確的遷移和最終的定位。神經(jīng)元遷移的方式主要包括兩種,即錐體細(xì)胞的放射狀遷移和中間神經(jīng)元的切線移位,其中放射狀遷移是主要的遷移方式,是形成神經(jīng)系統(tǒng)典型層狀結(jié)構(gòu)的基礎(chǔ),也是神經(jīng)系統(tǒng)形成復(fù)雜功能的前提。在大腦皮層發(fā)育早期,皮質(zhì)較薄、遷移的距離較短時,此時錐體神經(jīng)元是借助胞體位移的方式進(jìn)行放射狀遷移；而在發(fā)育晚期,皮質(zhì)較厚、遷移較長的距離時,錐體神經(jīng)元則是借助呈放射狀的膠質(zhì)細(xì)胞導(dǎo)向作用從原始部位遷移至相應(yīng)大腦皮層。然而其遷移過程的具體機(jī)制仍然不清。目前,國內(nèi)外研究顯示,眾多分子參與神經(jīng)元放射狀遷移過程。

1 神經(jīng)元放射狀遷移

神經(jīng)元祖細(xì)胞在腦室?guī)?ventricular zone, VZ)生成并完成終末分裂后即開始向外遷移至最適皮質(zhì)層。VZ產(chǎn)生的新神經(jīng)元沿著呈放射狀排列的膠質(zhì)纖維逐漸向大腦皮層遷移。人類的大腦皮層層狀結(jié)構(gòu)分為6層,按神經(jīng)元形成先后以從內(nèi)到外(inside-out)的順序形成,即前期生成的神經(jīng)元位于皮層的深層,后期產(chǎn)生的新神經(jīng)元跨越已形成的層狀結(jié)構(gòu)位于淺層。VZ中不對稱的神經(jīng)祖細(xì)胞遷移形成前板層(preplate, PP),最早期PP中的神經(jīng)元形成皮質(zhì)板層(cortical plate, CP)(第Ⅵ層神經(jīng)元),而將PP分為了底板(subplate, SP)和邊緣帶(marginal zone, MZ),緊接著VZ生成的神經(jīng)元遷移經(jīng)中間帶(intermediate zone, IZ)至CP并跨域第Ⅵ層形成第Ⅴ層皮質(zhì)層,依次類推,逐漸形成Ⅱ～Ⅳ層[1],這種內(nèi)-外的模式是人類進(jìn)化過程中所獲得的,是人類所特有的[2]。神經(jīng)元放射狀遷移為大腦行使其復(fù)雜功能提供了保障,其異常將導(dǎo)致多種疾病,如癲、精神分裂癥、無腦回畸形、智力低下等[3-5]。研究神經(jīng)元放射狀遷移機(jī)制已成為近年來研究的熱門話題,如研究發(fā)現(xiàn)腎上腺皮質(zhì)激素(doublecortin)、絲裂原活化蛋白激酶(MAPK-upstream protein kinase, MUK)、絲氨酸/蘇氨酸激酶(jun N-terminal kinases, JNK)、腦信號蛋白3A(semaphorin-3A, Sema3A)[6-7]等均與神經(jīng)元放射狀遷移有關(guān)。目前越來越多的相關(guān)分子得以挖掘,本文對新近發(fā)現(xiàn)的抑制、促進(jìn)神經(jīng)元放射狀遷移的相關(guān)分子進(jìn)行綜述。

2 抑制神經(jīng)元放射狀遷移的相關(guān)分子

2.1 唐氏綜合征細(xì)胞黏附分子(Down syndrome cell adhesion molecule, DSCAM)

DSCAM是在唐氏綜合征患者中新發(fā)現(xiàn)的神經(jīng)元黏附分子,是一種新的免疫球蛋白超家族。在人類其基因位于21q22.2～22.3[8],脊椎動物有兩型橫向同源物: DSCAM和DSCAML1(DSCAM-like-1),二者編碼的蛋白在中樞神經(jīng)系統(tǒng)廣泛表達(dá),如海馬、小腦、脊髓、視網(wǎng)膜神經(jīng)突等[9-10]。該基因保守域結(jié)構(gòu)由10個免疫球蛋白域,6個重復(fù)Ⅲ型纖連蛋白,1個跨膜域和胞質(zhì)尾的c末端組成[11]。DSCAM在發(fā)育神經(jīng)系統(tǒng)中對樹突形成、自我回避、軸突導(dǎo)向、軸突目標(biāo)識別和突觸形成扮演著十分重要的角色[12]。過表達(dá)海馬神經(jīng)元中的DSCAM會抑制樹突的分枝,且含有DSCAM mRNA和蛋白的樹突數(shù)增加了,DSCAM樹突的翻譯受N-甲基-D-天冬氨酸(N-methyl-D-aspartate, NMDA)的誘導(dǎo),因此DSCAM導(dǎo)致唐氏綜合征中樹突形態(tài)及突觸塑造的改變可能是通過NMDA介導(dǎo)發(fā)生[13]。NMDA受體是一種興奮性氨基酸受體[14],在人體中發(fā)揮著重要作用,目前已知NMDA能夠調(diào)節(jié)神經(jīng)元放射狀遷移。DSCAM與神經(jīng)元放射狀遷移有關(guān)是近年來研究的熱點(diǎn)。Zhang等[9]通過在體胚胎子宮內(nèi)電轉(zhuǎn)染基因(in utero electroporation),將DSCAM的干擾RNA(RNA interference,RNAi)(此種RNA能抑制特定基因的表達(dá)[15])轉(zhuǎn)入側(cè)腦室對DSCAM進(jìn)行敲減,發(fā)現(xiàn)表達(dá)shDSCAM的神經(jīng)元不能正確遷移至皮質(zhì)Ⅱ/Ⅲ層,停留在更深的皮質(zhì)層及IZ中。無論在哪個階段(出生后第0、7天)皮質(zhì)Ⅱ/Ⅲ層的DSCAM神經(jīng)元都較對照組明顯減少,減弱其表達(dá),抑制了皮層神經(jīng)元遷移至目的地。Shen等[3]研究了35個耐藥性癲(intractable epilepsy, IE)患者,發(fā)現(xiàn)DSCAM在IE中的表達(dá)較對照組明顯增多。而神經(jīng)元遷移異常與IE也相關(guān),這些間接說明DSCAM與神經(jīng)元遷移之間存在相關(guān)性。

2.2 糖原合成激酶-3(glycogen synthase kinase, GSK-3)

GSK-3是一種普遍存在的絲/蘇氨酸蛋白激酶,因在葡萄糖代謝中起關(guān)鍵調(diào)節(jié)酶的作用而被發(fā)現(xiàn)。其作用底物眾多,在體內(nèi)作用非常廣泛,參與多種信號通路,如磷脂酰肌醇三激酶/磷酸酶(phospho-inositide 3-kinase(PI3K)/phosphatase)、PTEN/AKt/mTORC1(tensin homolog/AKt/mammalian target of rapamycin complex 1)、Wnt/β-連環(huán)素蛋白通道(Wnt/β-catenin signaling)[16],調(diào)節(jié)新陳代謝、細(xì)胞分化、免疫及細(xì)胞的生存和死亡,主要由兩種亞型組成,即GSK-3α和GSK-3β[17],二者雖由不同的基因編碼,但二者的結(jié)構(gòu)域98%是相同的,并且大多數(shù)情況下,具有相似的功能[18],已發(fā)現(xiàn)GSK-3與多種疾病相關(guān),如心力衰竭、雙相障礙、糖尿病、阿爾茨海默病等[19]。在發(fā)育神經(jīng)系統(tǒng)中,GSK-3通過調(diào)節(jié)β-catenin和NFAT轉(zhuǎn)錄因子調(diào)控軸突的生長,進(jìn)而參與神經(jīng)元的極化,并能促神經(jīng)元的分化。GSK-3的缺失增強(qiáng)了祖細(xì)胞的增殖。目前,GSK-3在神經(jīng)元放射狀遷移中有何作用及機(jī)制目前尚不明確。研究[20]發(fā)現(xiàn)抑制GSK3的表達(dá)可以明顯抑制神經(jīng)元的放射狀遷移。這種受GSK-3調(diào)節(jié)的放射狀遷移是獨(dú)立于Wnt/β-連環(huán)素蛋白通道,與微管調(diào)節(jié)蛋白的磷酸化相關(guān)。

2.3 解整合素金屬蛋白酶17(adisintegrin and metalloprotease 17, ADAM17)

ADAM17也稱腫瘤壞死因子α轉(zhuǎn)換酶,是一種Ⅰ型跨膜金屬蛋白酶,參與數(shù)種跨膜蛋白的細(xì)胞外領(lǐng)域的脫落,如細(xì)胞因子、趨化因子、生長因子及其受體等[21]。ADAM17作用的底物廣泛,參與了眾多疾病的發(fā)生發(fā)展,如非小細(xì)胞肺癌[22]、卵巢癌[23]、炎癥性腸病[24]、急性肺炎[25]、阿爾茨海默病和唐氏綜合征[26]。ADAM17能反式激活表皮生長因子受體(epidermal growth factor receptor, EGFR)[27],強(qiáng)制性表達(dá)ADAM17,增強(qiáng)EGFR的磷酸化[28]。ADAM17-EGFR信號軸對維持產(chǎn)后表皮屏障的平衡發(fā)揮重要的作用[29]。研究[30]發(fā)現(xiàn),EGFR參與神經(jīng)元的放射狀遷移。Li等[31]應(yīng)用在體胚胎子宮內(nèi)電轉(zhuǎn)染基因術(shù)在C57BL/6小鼠懷孕后14.5d時敲減和過表達(dá)ADAM17,結(jié)果發(fā)現(xiàn)在懷孕后16.5d時敲減ADAM17的神經(jīng)元其放射狀遷移未受影響,正常遷移至IZ區(qū)；在懷孕后18.5d時大部分轉(zhuǎn)染的神經(jīng)元停止遷移至CP區(qū)而停留在IZ區(qū),并發(fā)現(xiàn)這種遷移的破壞可部分通過過表達(dá)抵抗ADAM17的shRNA而得到拯救,而單獨(dú)過表達(dá)ADAM17時放射狀遷移并不受影響。

3 促進(jìn)神經(jīng)元放射狀遷移的相關(guān)分子

3.1 遷移抑制蛋白(migration inhibitory protein, MINP)

MINP是一種新鑒定的神經(jīng)元遷移抑制蛋白,能夠負(fù)性調(diào)節(jié)神經(jīng)元的放射狀遷移。MINP mRNA在中樞神經(jīng)系統(tǒng)和周圍神經(jīng)系統(tǒng)都有表達(dá),在大腦皮層中含量豐富。該基因位于染色體16p13.11,在16p13.11區(qū)域中有缺失的人與癲、智能障礙、精神分裂癥、自閉癥、注意力缺陷多動癥等有關(guān),因而此區(qū)域內(nèi)的基因功能改變與精神類疾病密切相關(guān),核分布基因E同系物1(nuclear distribution gene E homologue 1, NDE1)亦位于16p13.11區(qū)域,敲減NDE1鼠發(fā)育成了更小的大腦皮質(zhì),說明NDE1是16p13.11區(qū)域內(nèi)相關(guān)神經(jīng)精神疾病的候選基因。然而研究發(fā)現(xiàn)NDE1同型突變的患者表現(xiàn)出遷移嚴(yán)重受損,其雜合突變的患者沒有患精神類疾病,因而推測在16p13.11區(qū)域還存在著其他的候選基因。因而,MINP被認(rèn)為是神經(jīng)發(fā)育疾病的候選基因。通過在體胚胎子宮內(nèi)電轉(zhuǎn)染基因的方法,敲減及過表達(dá)MINP,發(fā)現(xiàn)敲減MINP增加神經(jīng)元的放射狀遷移,而MINP過表達(dá)則減少了神經(jīng)元的放射狀遷移,說明MINP調(diào)節(jié)神經(jīng)元的放射狀遷移具有自主性,并且發(fā)現(xiàn)這種潛在的調(diào)節(jié)機(jī)制可能與微管蛋白有關(guān)[32]。

3.2 一氧化氮合酶1接頭蛋白(nitric oxide synth-ase 1 adaptor protein, NOS1AP)

NOS1AP基因位于1q23.3,編碼的胞質(zhì)蛋白(NOS1AP)能夠結(jié)合信號分子神經(jīng)型一氧化氮合酶(neuronal nitric oxide synthase, nNOS)[33],因此稱作nNOS的接頭蛋白。NOS1AP是NMDA受體驅(qū)動的nNOS(NMDAR-driven nNOS)功能的抑制劑,因而在由NMDA受體介導(dǎo)的興奮毒性中具有神經(jīng)保護(hù)作用[34],目前,很多研究在精神疾病和心臟病患者中發(fā)現(xiàn)了NOS1AP的單核苷酸多態(tài)性作用,如創(chuàng)傷后應(yīng)激障礙、抑郁癥、急性心肌梗死、長QT綜合征[35-36]。NOS1AP是精神分裂癥的易感基因[37],而神經(jīng)元放射狀遷移的異常將導(dǎo)致精神分裂癥。Damien等[4]發(fā)現(xiàn)，NOS1AP的過表達(dá)破壞了神經(jīng)元放射狀遷移,神經(jīng)元更多的停留在了中間板層,而敲減NOS1AP反而增加了CP中的神經(jīng)元,并且發(fā)現(xiàn)具有減少樹突數(shù)量作用的NOS1AP的第181位到307位的氨基酸對神經(jīng)元放射狀遷移無影響。

4 結(jié) 語

在大腦皮層發(fā)育中,神經(jīng)元經(jīng)放射狀遷移至適宜的CP層形成經(jīng)典的板層結(jié)構(gòu),這是大腦行使復(fù)雜精細(xì)功能的前提。神經(jīng)元放射狀遷移受多種分子的調(diào)節(jié),然而神經(jīng)元如何這么準(zhǔn)確無誤的沿著一個主導(dǎo)方向經(jīng)過長距離遷移至目的地仍絕大部分是未知的,是未來研究的方向。對神經(jīng)元遷移的分子機(jī)制研究將為診治神經(jīng)相關(guān)疾病帶來希望。

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Research progress on related molecules on radial migration of neurons

JIANGHua-yu1,WANGYong-gang2

(1. Dept. of Neurology, Yangpu Hospital, Tongji University, Shanghai 200090, China;2. Dept. of Neurology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China)

Radial migration is the major way of the migration of neurons, which is important for the formation of brain cortical layers. Recently researches focus on the related molecules of cell radial migration, which are consist of two types: one type inhibits the radial migration when knocked down and another enhances the radial migration when knocked down.

cell radial migration; inhibit; enhance

10.16118/j.1008-0392.2016.01.027

2014-03-06

國家自然科學(xué)基金項目(010212036)

蔣華玉(1984—),女,住院醫(yī)師,碩士.E-mail: jhuayu1986@163.com

王永剛.E-mail: w100yg@163.com

R 744

A

1008-0392(2016)01-0124-05