常染色體隱性遺傳小頭畸形相關(guān)蛋白研究進(jìn)展

王玉杰，周小坤，徐丹

綜述

常染色體隱性遺傳小頭畸形相關(guān)蛋白研究進(jìn)展

王玉杰，周小坤，徐丹

福州大學(xué)生物科學(xué)與工程學(xué)院，福州 350108

腦發(fā)育相關(guān)疾病是一類(lèi)影響大腦或中樞神經(jīng)系統(tǒng)生長(zhǎng)和發(fā)育的疾病。常染色體隱性遺傳小頭畸形(autosomal recessive primary microcephaly, MCPH)是一種神經(jīng)系統(tǒng)發(fā)育障礙疾病，病人主要表現(xiàn)為頭圍減小，并伴隨一定程度的智力衰退。迄今為止已發(fā)現(xiàn)至少有25個(gè)基因突變都會(huì)導(dǎo)致MCPH，根據(jù)它們發(fā)現(xiàn)的順序分別命名為~。MCPH蛋白作為重要的成份參與調(diào)控大腦發(fā)育相關(guān)信號(hào)通路。本文對(duì)目前發(fā)現(xiàn)的25個(gè)MCPH相關(guān)蛋白的表達(dá)模式、細(xì)胞定位、分子生物學(xué)功能、表型及動(dòng)物模型進(jìn)行了綜述，旨在提升人們對(duì)腦發(fā)育相關(guān)疾病的致病機(jī)制的認(rèn)知，促進(jìn)對(duì)神經(jīng)元生成、腦尺寸大小及腦功能調(diào)控等分子機(jī)制的研究。

小頭畸形；表達(dá)模式；細(xì)胞組分；表型概述；分子生物學(xué)功能；動(dòng)物模型

大腦是人體最重要和最復(fù)雜的器官，擁有上千億個(gè)神經(jīng)元和彼此間相互作用形成的百萬(wàn)億個(gè)連接點(diǎn)。大腦通過(guò)形成龐大而復(fù)雜的神經(jīng)網(wǎng)絡(luò)控制著其他器官或系統(tǒng)的正常功能。理解大腦的運(yùn)轉(zhuǎn)機(jī)制，是人類(lèi)與科學(xué)屆面臨的最偉大的挑戰(zhàn)之一。腦科學(xué)是21世紀(jì)各種前沿科學(xué)中最為引人關(guān)注的領(lǐng)域之一，同時(shí)也是多學(xué)科交叉的重要前沿科學(xué)領(lǐng)域。2013年，美國(guó)啟動(dòng)“腦計(jì)劃”旨在探索人類(lèi)大腦工作機(jī)制，繪制腦活動(dòng)全圖，并最終開(kāi)發(fā)出針對(duì)大腦疾病的療法。2018年以來(lái)，“北京腦科學(xué)中心”和“上海腦科學(xué)中心”相繼成立，標(biāo)志著“中國(guó)腦計(jì)劃”也正式拉開(kāi)了帷幕。

腦發(fā)育異常會(huì)導(dǎo)致其功能異常，并最終導(dǎo)致嚴(yán)重的神經(jīng)疾病如自閉癥、精神分裂癥及小頭癥等[1~7]。小頭癥即小頭畸形(microcephaly)是一種比較罕見(jiàn)的大腦疾病，是由于大腦神經(jīng)系統(tǒng)發(fā)育障礙導(dǎo)致的，發(fā)病率在2~12/萬(wàn)[8]。胎兒出生后的頭圍測(cè)量是診斷小頭癥最常用的方式之一[8]。診斷小頭癥的臨床標(biāo)準(zhǔn)是病人的頭圍相對(duì)于其同年齡與性別的平均值明顯小2個(gè)標(biāo)準(zhǔn)差以上[9]。通常在孕28周左右應(yīng)用超聲波技術(shù)和核磁共振掃描檢測(cè)即可發(fā)現(xiàn)患兒的頭圍測(cè)量值及腦容量低于正常同齡胎兒。小頭癥的主要表現(xiàn)是腦的重量明顯輕于正常、腦回過(guò)小或根本無(wú)腦回、大腦的發(fā)育明顯遲緩，甚至在嬰兒第3~5個(gè)月時(shí)就停止發(fā)育，最后導(dǎo)致患兒的頭頂變得小而尖、鼻梁凹陷、耳大、下額后縮、前額狹小并且頭圍明顯小于正常嬰兒，最大的頭圍不足43 cm。小頭癥患兒大腦發(fā)育障礙常常伴有不同程度的智力低下，有的患兒還會(huì)出現(xiàn)癲癇、運(yùn)動(dòng)障礙、語(yǔ)言障礙及其他行為異常[10]。造成小頭癥的原因有很多，大致可分成兩類(lèi)：一類(lèi)是由遺傳因素引起，即染色體或基因突變所導(dǎo)致；另一類(lèi)是由環(huán)境因素引起，即胎兒在妊娠早期受到各種有害因素影響包括營(yíng)養(yǎng)不良、中毒、物理或化學(xué)影響以及子宮感染(弓形蟲(chóng)病，風(fēng)疹，皰疹，梅毒，巨細(xì)胞病毒及艾滋病毒)所導(dǎo)致。2015年，一種蟲(chóng)媒病毒(寨卡病毒)在美洲和熱帶地區(qū)爆發(fā)導(dǎo)致小頭癥新生兒的大量產(chǎn)生引發(fā)了全世界的關(guān)注[11]。通過(guò)動(dòng)物模型驗(yàn)證，科學(xué)家已經(jīng)證實(shí)寨卡病毒感染確實(shí)會(huì)導(dǎo)致小頭癥的發(fā)生[12~14]。

常染色體隱性遺傳小頭畸形(autosomal recessive primary microcephaly, MCPH)是一種比較少見(jiàn)的神經(jīng)分裂異常引起的腦發(fā)育疾病。病人主要表現(xiàn)為頭圍減小并伴有不同程度的智力衰退[8]。目前發(fā)現(xiàn)的與MCPH有關(guān)的25個(gè)基因包括：()、()、()、()、()、()、()、()、()、()、()、()、()、()、()、()、()、()、()、()、()、()、()、()和()[15]。全世界范圍內(nèi)，超過(guò)50%的MCPH患者是由于()和)基因突變?cè)斐傻腫8]。本文通過(guò)查詢(xún)小鼠基因組信息(Mouse Genome Informatics, MGI)和美國(guó)國(guó)立生物技術(shù)信息中心(National Center for Biotechnology Information, NCBI)數(shù)據(jù)庫(kù)對(duì)已命名的25個(gè)MCPH相關(guān)蛋白的表達(dá)模式、細(xì)胞定位、分子生物學(xué)功能、表型及動(dòng)物模型等進(jìn)行了綜述，旨在提升人們對(duì)MCPH發(fā)病機(jī)制的認(rèn)知并加深人們對(duì)神經(jīng)元生成及腦尺寸大小調(diào)控機(jī)理的理解。

1 MCPH基因的時(shí)空特異性表達(dá)

結(jié)合MGI和NCBI網(wǎng)站數(shù)據(jù)分析發(fā)現(xiàn)，相關(guān)基因存在非常明顯的時(shí)空特異性表達(dá)(圖1，圖2)。MCPH作為一類(lèi)神經(jīng)發(fā)育疾病相關(guān)蛋白，大多數(shù)與細(xì)胞分裂相關(guān)，因此在細(xì)胞分裂活躍的組織表達(dá)較高。MGI數(shù)據(jù)庫(kù)(基于免疫組化和RNA原位雜交結(jié)果)結(jié)果顯示，有21個(gè)基因都在神經(jīng)系統(tǒng)表達(dá)，僅和未在神經(jīng)系統(tǒng)中檢測(cè)到表達(dá)。除神經(jīng)系統(tǒng)外，大部分在視覺(jué)系統(tǒng)、生殖系統(tǒng)和消化系統(tǒng)中也有表達(dá)。NCBI數(shù)據(jù)(基于正常組織RNAseq)顯示在人體組織中，已發(fā)現(xiàn)的25個(gè)中有11個(gè)基因在睪丸(相對(duì)其他組織)中表達(dá)量最高，分別是()、()、()、()、(STIL)、(Cep152)、()、(MFSD2A)、(ANKLE2)、()和()。另外，還有4個(gè)基因在睪丸(相對(duì)其他組織)中表達(dá)量次高，其中包括()、(SAS-6)、(CIT)和()。主要原因可能是基因在分裂旺盛的組織表達(dá)較高，而睪丸在產(chǎn)生精子過(guò)程中首先會(huì)產(chǎn)生很多精原干細(xì)胞。

圖1 Mcph在小鼠不同組織的表達(dá)模式

根據(jù)小鼠基因組信息(Mouse Genome Informatics, MGI)數(shù)據(jù)庫(kù)總結(jié)得到22個(gè)基因在不同組織的表達(dá)模式。

此外，通過(guò)分析NCBI數(shù)據(jù)庫(kù)RNA-seq結(jié)果，將25個(gè)基因在小鼠腦發(fā)育不同階段的表達(dá)情況進(jìn)行匯總，結(jié)果發(fā)現(xiàn)大部分在腦發(fā)育早期(胚胎11.5天)表達(dá)量較高，隨著發(fā)育的進(jìn)行(胚胎18天)表達(dá)量逐漸下降，在成年腦皮質(zhì)中表達(dá)量更低甚至幾乎檢測(cè)不到(圖2)?；虻臅r(shí)空特異性表達(dá)決定其在調(diào)控腦發(fā)育和育性方面起著非常重要的作用。

2 MCPH蛋白在細(xì)胞中的定位

通過(guò)蛋白序列分析或結(jié)構(gòu)預(yù)測(cè)發(fā)現(xiàn)，大部分MCPH蛋白定位在細(xì)胞骨架和細(xì)胞核中(圖3)。中心體是微管組織中心，大部分MCPH蛋白都定位在有絲分裂裝置如中心體或紡錘體上[16]。在腦發(fā)育過(guò)程中，中心體和紡錘體的正確組裝對(duì)于產(chǎn)生和維持正常的神經(jīng)細(xì)胞的數(shù)量起著非常關(guān)鍵的作用。MCPH蛋白缺失或突變會(huì)干擾中心體或紡錘體的正常形成，影響細(xì)胞周期及DNA復(fù)制等過(guò)程，進(jìn)而影響神經(jīng)前體細(xì)胞的增殖、分化和凋亡等過(guò)程，最終導(dǎo)致神經(jīng)元數(shù)量減少并形成偏小的大腦[17~20]。MCPH2/WDR62表現(xiàn)出非常明顯的細(xì)胞周期依賴(lài)性表達(dá)。在有絲分裂中期或前中期，WDR62主要集中在紡錘體極點(diǎn)，而在有絲分裂間期WDR62則彌散地分布在細(xì)胞質(zhì)中[21]。在細(xì)胞有絲分裂間期，高爾基體是除中心體外的另一個(gè)微管組織中心。有些MCPH蛋白定位在高爾基體上，如MCPH3 (CDK5RAP2)通過(guò)ATP及中心體依賴(lài)的形式定位在高爾基體上[22]。MCPH19 (COPB2，β-輔酶亞基)以GTP依賴(lài)形式結(jié)合在高爾基體膜上并對(duì)高爾基體的形成及囊泡運(yùn)輸過(guò)程起重要作用[23]。還有些MCPH蛋白(MCPH15/MFSD2A和MCPH16/ANKLE2)則定位在內(nèi)質(zhì)網(wǎng)上[24,25](圖3)。

圖2 Mcph基因在小鼠腦發(fā)育不同階段的表達(dá)情況

根據(jù)美國(guó)國(guó)立生物技術(shù)信息中心(National Center for Biotechnology Information, NCBI)數(shù)據(jù)庫(kù)總結(jié)得到不同基因在小鼠不同發(fā)育階段中樞神經(jīng)系統(tǒng)的表達(dá)情況。藍(lán)色不同強(qiáng)度代表表達(dá)強(qiáng)弱，越接近藍(lán)色表達(dá)越強(qiáng)，越接近白色表達(dá)越弱。

3 MCPH蛋白參與的生物學(xué)過(guò)程

動(dòng)物個(gè)體發(fā)育是一個(gè)復(fù)雜而精細(xì)的過(guò)程。大部分MCPH蛋白在發(fā)育過(guò)程參與細(xì)胞成分組裝進(jìn)而調(diào)控細(xì)胞的增殖分化及系統(tǒng)發(fā)育等過(guò)程(圖4)。大腦的大小是通過(guò)調(diào)節(jié)神經(jīng)干細(xì)胞增殖、分化和凋亡的平衡來(lái)控制的[26]。目前研究得比較多的一些MCPH蛋白(如MCPH5/ASPM、MCPH2/WDR62和MCPH6/ CENPJ等)在神經(jīng)干細(xì)胞的增殖或分化過(guò)程中起著重要作用[20,27~30]。神經(jīng)遷移與神經(jīng)發(fā)生和大腦尺寸調(diào)控密切相關(guān)。在大腦皮層形成過(guò)程中，正常的神經(jīng)遷移是至關(guān)重要的一個(gè)環(huán)節(jié)，是構(gòu)成大腦皮層復(fù)雜的組織結(jié)構(gòu)及特殊回路的前提和基礎(chǔ)。一些MCPH蛋白(如MCPH5和MCPH6)參與調(diào)控大腦皮層神經(jīng)細(xì)胞的遷移[27,28]。一些MCPH蛋白(如MCPH1)則參與調(diào)控細(xì)胞凋亡或DNA損傷過(guò)程[31]。一些MCPH蛋白(如MCPH2/WDR62、MCPH3/ CDK5RAP2和MCPH5/ASPM)參與調(diào)控微管的組裝、聚合或解聚[32~34]。MCPH7/STIL參與小鼠胚胎體軸的特化和神經(jīng)管的發(fā)育[35]。MCPH18/WDFY3通過(guò)調(diào)控自噬過(guò)程來(lái)影響大腦發(fā)育[36]。

4 MCPH突變表型

4.1 MCPH突變病人的表型

MCPH病人一般比較矮小，身高和體重亦低于正常值下限。MCPH是一種神經(jīng)發(fā)育障礙疾病，并且大部分基因在神經(jīng)系統(tǒng)高表達(dá)，因此基因突變病人的表型主要集中在神經(jīng)系統(tǒng)(圖5)。大腦體積減小和皮質(zhì)發(fā)育不良是MCPH病人的主要特征。同時(shí)一些MCPH病人還表現(xiàn)出小腦、腦干及胼胝體發(fā)育不良[15]。MCPH病人在行為上主要表現(xiàn)為不同程度的智力障礙，部分表現(xiàn)出運(yùn)動(dòng)及語(yǔ)言障礙，也有部分病人表現(xiàn)出共濟(jì)失調(diào)、癲癇及先天性耳聾等癥狀[37~39]。

圖3 MCPH蛋白的細(xì)胞定位

根據(jù)小鼠基因組信息(Mouse Genome Informatics, MGI)數(shù)據(jù)庫(kù)總結(jié)得到25個(gè)MCPH蛋白在不同細(xì)胞組分中的定位。

有絲分裂過(guò)程和分離缺陷、微管和紡錘體異常以及DNA損傷和細(xì)胞周期異常等過(guò)程在病人來(lái)源或基因突變的細(xì)胞中被發(fā)現(xiàn)[21,40~44]。也有研究表明由于神經(jīng)前體細(xì)胞中RNA加工模式的不同是導(dǎo)致MCPH突變影響神經(jīng)系統(tǒng)的原因[45]。根據(jù)MGI數(shù)據(jù)庫(kù)顯示大部分突變會(huì)影響有絲分裂引起不同組織的多種表型，同時(shí)也會(huì)影響減數(shù)分裂引起生殖系統(tǒng)出現(xiàn)問(wèn)題(圖5)。

4.2 MCPH相關(guān)動(dòng)物模型的構(gòu)建

研究MCPH蛋白功能的動(dòng)物模型主要有斑馬魚(yú)()、果蠅()和小鼠()。MCPH除在神經(jīng)系統(tǒng)發(fā)育上表現(xiàn)出小頭癥的表型外，在個(gè)體生長(zhǎng)發(fā)育過(guò)程中也起著重要作用(表1)。另外，MCPH蛋白在生殖系統(tǒng)中高表達(dá)，因此，MCPH蛋白缺失會(huì)導(dǎo)致小鼠生殖細(xì)胞發(fā)育缺陷進(jìn)而引起育性降低，甚至不育[46~49]。近年來(lái)，有研究表明缺失也會(huì)影響小鼠聽(tīng)力并引發(fā)中耳炎[50]。由于MCPH蛋白對(duì)動(dòng)物生長(zhǎng)發(fā)育的關(guān)鍵作用，一些MCPH蛋白缺失甚至?xí)?dǎo)致動(dòng)物胚胎致死或細(xì)胞凋亡?；蚯贸∈蟮臉?gòu)建為表型分析和MCPH致病機(jī)制的研究提供了有效的動(dòng)物模型。但由于小鼠大腦與人腦相比沒(méi)有腦回結(jié)構(gòu)及更多類(lèi)型的神經(jīng)前體細(xì)胞，基因敲除小鼠有時(shí)不能很好地模擬小頭癥的表型。2016年，科學(xué)家利用TALEN技術(shù)制備了突變體食蟹猴()，等位基因突變食蟹猴表現(xiàn)出頭圍減小、胼胝體發(fā)育不良以及上肢痙攣等特征模擬了大部分小頭癥病人的臨床表型[51]。近年來(lái)有研究在雪貂()中敲除，敲除雪貂表現(xiàn)出更為明顯的小頭癥表型[52]。

圖4 MCPH蛋白參與的生物學(xué)過(guò)程

根據(jù)小鼠基因組信息(Mouse Genome Informatics, MGI)數(shù)據(jù)庫(kù)總結(jié)得到25個(gè)MCPH蛋白參與的生物學(xué)過(guò)程。

圖5 Mcph基因突變相關(guān)表型

根據(jù)小鼠基因組信息(Mouse Genome Informatics, MGI)數(shù)據(jù)庫(kù)總結(jié)得到25個(gè)基因突變的表型。

表1 MCPH相關(guān)動(dòng)物模型

續(xù)表

5 MCPH分子機(jī)制研究

5.1 MCPH蛋白功能預(yù)測(cè)

MCPH蛋白分子的功能是多樣化的。根據(jù)MGI網(wǎng)站生物信息學(xué)分析預(yù)測(cè)一些MCPH蛋白如MCPH3、MCPH6、MCPH13、MCPH20和MCPH25主要參與結(jié)合細(xì)胞骨架蛋白。一些MCPH蛋白結(jié)合DNA (MCPH3、MCPH10和MCPH11)和糖類(lèi)及其衍生物(MCPH12、MCPH13、MCPH17和MCPH20)；還有一些蛋白則作為各種酶如水解酶(MCPH13和MCPH20)、轉(zhuǎn)移酶(MCPH6、MCPH12、MCPH17和MCPH18)催化各種生物化學(xué)反應(yīng)來(lái)調(diào)控生物體內(nèi)的新陳代謝和能量轉(zhuǎn)換(圖6)。

5.2 MCPH參與的信號(hào)通路

MCPH蛋白通常調(diào)控細(xì)胞周期，因此很多MCPH蛋白都參與細(xì)胞周期相關(guān)信號(hào)通路的調(diào)控。MCPH1通過(guò)Chk1–Cdc25–Cdk1調(diào)控中心體及紡錘體的形成進(jìn)而調(diào)控神經(jīng)前體細(xì)胞的分裂[53]。MCPH1/ BRIT1還可以與E2F1結(jié)合調(diào)控CHK1和BRCA1參與DNA修復(fù)和細(xì)胞凋亡調(diào)控[71]。MCPH2/WDR62通過(guò)JNK信號(hào)通路調(diào)控神經(jīng)前體細(xì)胞的增殖和分化[20]。同時(shí)，MEKK3和FBW7雙向調(diào)控WDR62蛋白的穩(wěn)定性進(jìn)而調(diào)控大腦皮層神經(jīng)干細(xì)胞穩(wěn)態(tài)平衡[72]。MCPH3/CDK5RAP2與EB1結(jié)合調(diào)控微管的動(dòng)態(tài)組裝[32]。MCPH5/ASPM通過(guò)Wnt信號(hào)通路調(diào)控神經(jīng)前體細(xì)胞的增殖和分化[27]。MCPH6/CPAP在大腦發(fā)育過(guò)程中作用于A(yíng)scl1下游來(lái)調(diào)控神經(jīng)前體細(xì)胞的分裂及神經(jīng)遷移[28]。MCPH7通過(guò)調(diào)控Sonic hedgehog (Shh)信號(hào)通路來(lái)調(diào)控胚胎體軸的發(fā)育[36]。MCPH9/CEP152與PLK4結(jié)合調(diào)控中心粒的復(fù)制[52]。MCPH9/CEP152和MCPH17/CITK被報(bào)道與p53信號(hào)通路相關(guān)[47,67]。MCPH18/ALFY通過(guò)調(diào)控自噬來(lái)調(diào)控經(jīng)典Wnt信號(hào)通路[35]。MCPH19/COPB2通過(guò)上調(diào)YAP表達(dá)來(lái)調(diào)控細(xì)胞增殖[73]。

圖6 MCPH蛋白的分子生物學(xué)功能

根據(jù)小鼠基因組信息(Mouse Genome Informatics, MGI)數(shù)據(jù)庫(kù)總結(jié)得到25個(gè)MCPH蛋白的分子生物學(xué)功能。

6 結(jié)語(yǔ)與展望

現(xiàn)代人大腦的尺寸大小約是3百萬(wàn)年前人類(lèi)祖先南方古猿人大腦的3倍，特別是大腦皮層及腦回?cái)?shù)量增加達(dá)100倍[74]。大腦的尺寸大小及結(jié)構(gòu)復(fù)雜度的增加必然伴隨認(rèn)知功能的增加[75]。由于大腦的尺寸大小及腦回?cái)?shù)量與神經(jīng)元的數(shù)量密切相關(guān)，因此研究那些影響神經(jīng)細(xì)胞增殖、分化及凋亡的基因有利于了解腦發(fā)育過(guò)程及人類(lèi)的進(jìn)化過(guò)程。MCPH是一種常染色體隱性遺傳小頭畸形病癥。本文對(duì)已報(bào)道的25個(gè)MCPH蛋白的表達(dá)、定位和功能進(jìn)行了總結(jié)和概述，為研究大腦發(fā)育相關(guān)蛋白特別是MCPH蛋白的致病機(jī)制提供了理論依據(jù)和線(xiàn)索。在已報(bào)道的25個(gè)MCPH中，和突變導(dǎo)致的MCPH病人較多，因此相關(guān)研究也較多。同時(shí)根據(jù)被發(fā)現(xiàn)的順序，一些較早發(fā)現(xiàn)的MCPH蛋白(MCPH1~MCPH10)的動(dòng)物模型建立較多，而較晚發(fā)現(xiàn)的MCPH11~MCPH25只有少部分蛋白的動(dòng)物模型已經(jīng)建立。在已建立的動(dòng)物模型中，大部分MCPH缺失或突變模型都會(huì)導(dǎo)致小頭癥的典型特征即大腦明顯變小，還有一部分動(dòng)物模型影響了生殖系統(tǒng)。導(dǎo)致小頭癥的分子機(jī)制研究主要集中在調(diào)控中心體或紡錘體的形成進(jìn)而影響神經(jīng)前體細(xì)胞的增殖分化和細(xì)胞凋亡。也有一些MCPH突變小鼠表現(xiàn)出小腦發(fā)育不良或神經(jīng)元軸突發(fā)育異常。近年來(lái)，大腦類(lèi)器官的建立為研究大腦疾病包括小頭癥的發(fā)病機(jī)制提供了很好的模型[76,77]。Gabriel等[77,78]利用人iPSC誘導(dǎo)的類(lèi)腦模型研究MCPH6/CPAP的致病機(jī)制。鑒于大腦類(lèi)器官模型在體外培養(yǎng)的局限性，構(gòu)建小頭癥相關(guān)蛋白缺失或突變的動(dòng)物模型仍是未來(lái)研究小頭癥發(fā)病機(jī)制的有效手段。

大腦的尺寸在一定程度上反應(yīng)腦重量和腦容量的大小[79]。但是擁有一個(gè)更大的大腦并不意味著人類(lèi)或動(dòng)物在認(rèn)知方面就表現(xiàn)得更好。病人的頭圍相對(duì)于其同年齡與性別的平均值明顯大2個(gè)標(biāo)準(zhǔn)差以上會(huì)導(dǎo)致另外一種腦發(fā)育疾病稱(chēng)為巨腦癥(macro-cephaly)[80]。巨腦癥主要是由于神經(jīng)增殖和遷移異常引起，病人表現(xiàn)出智力低下并有部分伴有自閉癥樣行為[80~83]。因此，維持大腦尺寸的正常發(fā)育對(duì)于腦功能的正常發(fā)揮起著非常重要的作用。

[1] Thornton GK, Woods CG. Primary microcephaly: do all roads lead to Rome?, 2009, 25(11): 501– 510.

[2] Kang EC, Burdick KE, Kim JY, Duan X, Guo JU, Sailor KA, Jung DE, Ganesan S, Choi S, Pradhan D, Lu B, Avramopoulos D, Christian K, Malhotra AK, Song HJ, Ming GL. Interaction between FEZ1 and DISC1 in regulation of neuronal development and risk for schizophrenia., 2011, 72(4): 559–571.

[3] Kaindl AM, Passemard S, Kumar P, Kraemer N, Issa L, Zwirner A, Gerard B, Verloes A, Mani S, Gressens P. Many roads lead to primary autosomal recessive microcephaly., 2010, 90(3): 363–383.

[4] Gleeson JG. Neuronal migration disorders., 2001, 7(3): 167–171.

[5] Zhang H, Kang E, Wang Y, Yang C, Yu H, Wang Q, Chen Z, Zhang C, Christian KM, Song H, Ming GL, Xu Z. Brain-specific Crmp2 deletion leads to neuronal development deficits and behavioural impairments in mice., 2016, 7.

[6] Kim JY, Liu CY, Zhang FY, Duan X, Wen ZX, Song J, Feighery E, Lu B, Rujescu D, St Clair D, Christian K, Callicott JH, Weinberger DR, Song HJ, Ming GL. Interplay between DISC1 and GABA signaling regulates neurogenesis in Mice and Risk for schizophrenia., 2012, 148(5): 1051–1064.

[7] Dang T, Duan WY, Yu B, Tong DL, Cheng C, Zhang YF, Wu W, Ye K, Zhang WX, Wu M, Wu BB, An Y, Qiu ZL, Wu BL. Autism-associated dyrk1a truncation mutants impair neuronal dendritic and spine growth and interfere with postnatal cortical development., 2018, 23(3): 747–758.

[8] Mahmood S, Ahmad W, Hassan MJ. Autosomal recessive primary microcephaly (MCPH): clinical manifestations, genetic heterogeneity and mutation continuum., 2011, 6: 39.

[9] Woods CG, Parker A. Investigating microcephaly., 2013, 98(9): 707–713.

[10] McDonell LM, Warman Chardon J, Schwartzentruber J, Foster D, Beaulieu CL, FORGE Canada Consortium, Majewski J, Bulman DE, Boycott KM. The utility of exome sequencing for genetic diagnosis in a familial microcephaly epilepsy syndrome., 2014, 14: 22.

[11] Kruger RP. Zika virus on the move., 2016, 164(4): 585–587.

[12] Miner JJ, Cao B, Govero J, Smith AM, Fernandez E, Cabrera OH, Garber C, Noll M, Klein RS, Noguchi KK, Mysorekar IU, Diamond MS. Zika virus infection during pregnancy in mice causes placental damage and fetal demise., 2016, 165(5): 1081–1091.

[13] Li C, Xu D, Ye Q, Hong S, Jiang YS, Liu X, Zhang N, Shi L, Qin CF, Xu Z. Zika virus disrupts neural progenitor development and leads to microcephaly in mice., 2016, 19(5):120–126.

[14] Cugola FR, Fernandes IR, Russo FB, Freitas BC, Dias JLM, Guimar?es KP, Benazzato C, Almeida N, Pignatari GC, Romero S, Polonio CM, Cunha I, Freitas CL, Brand?o WN, Rossato C, Andrade DG, Faria Dde P, Garcez AT, Buchpigel CA, Braconi CT, Mendes E, Sall AA, Zanotto PM, Peron JP, Muotri AR, Beltr?o-Braga PC. The brazilian zika virus strain causes birth defects in experimental models., 2016, 534(7606): 267–271.

[15] Zaqout S, Morris-Rosendahl D, Kaindl AM. Autosomal recessive primary microcephaly (MCPH): an update., 2017, 48(3): 135–142.

[16] Megraw TL, Sharkey JT, Nowakowski RS. Cdk5rap2 exposes the centrosomal root of microcephaly syndromes., 2011, 21(8): 470–480.

[17] Manzini MC, Walsh CA. What disorders of cortical development tell us about the cortex: one plus one does not always make two., 2011, 21(3): 333–339.

[18] Cox J, Jackson AP, Bond J, Woods CG. What primary microcephaly can tell us about brain growth., 2006, 12(8): 358–366.

[19] Farag HG, Froehler S, Oexle K, Ravindran E, Schindler D, Staab T, Huebner A, Kraemer N, Chen W, Kaindl AM. Abnormal centrosome and spindle morphology in a patient with autosomal recessive primary microcephaly type 2 due to compound heterozygous, 2013, 8: 178.

[20] Xu D, Zhang F, Wang Y, Sun Y, Xu Z. Microcephaly- associated protein WDR62 regulates neurogenesis through JNK1 in the developing neocortex., 2014, 6(1): 104–116.

[21] Nicholas AK, Khurshid M, Désir J, Carvalho OP, Cox JJ, Thornton G, Kausar R, Ansar M, Ahmad W, Verloes A, Passemard S, Misson JP, Lindsay S, Gergely F, Dobyns WB, Roberts E, Abramowicz M, Woods CG. WDR62 is associated with the spindle pole and is mutated in human microcephaly., 2010, 42(11): 1010–1014.

[22] Wang Z, Wu T, Shi L, Zhang L, Zheng W, Qu JY, Niu R, Qi RZ. Conserved motif of CDK5RAP2 mediates its localization to centrosomes and the Golgi complex., 2010, 285(29): 22658–22665.

[23] Guo Y, Punj V, Sengupta D, Linstedt AD. Coat-tether interaction in golgi organization., 2008, 19(7): 2830–2843.

[24] Guemez-Gamboa A, Nguyen LN, Yang H, Zaki MS, Kara M, Ben-Omran T, Akizu N, Rosti RO, Rosti B, Scott E, Schroth J, Copeland B, Vaux KK, Cazenave-Gassiot A, Quek DQ, Wong BH, Tan BC, Wenk MR, Gunel M, Gabriel S, Chi NC, Silver DL, Gleeson JG. Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome., 2015, 47(7): 809–813.

[25] Gaudet P, Livstone MS, Lewis SE, Thomas PD. Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium., 2011, 12(5): 449–462.

[26] Woods CG, Bond J, Enard W. Autosomal recessive primary microcephaly (MCPH): A review of clinical, molecular, and evolutionary findings., 2005, 76(5): 717–728.

[27] Buchman JJ, Durak O, Tsai LH. ASPM regulates Wnt signaling pathway activity in the developing brain., 2011, 25(18): 1909–1914.

[28] Garcez PP, Diaz-Alonso J, Crespo-Enriquez I, Castro D, Bell D, Guillemot F. Cenpj/CPAP regulates progenitor divisions and neuronal migration in the cerebral cortex downstream of ascl1., 2015, 6: 6474.

[29] Jayaraman D, Kodani A, Gonzalez DM, Mancias JD, Mochida GH, Vagnoni C, Johnson J, Krogan N, Harper JW, Reiter JF, Yu TW, Bae BI, Walsh CA. Microcephaly proteins Wdr62 and aspm define a mother centriole complex regulating centriole biogenesis, apical complex, and cell fate., 2016, 92(4): 813–828.

[30] Chen JF, Zhang Y, Wilde J, Hansen KC, Lai F, Niswander L. Microcephaly disease gene Wdr62 regulates mitotic progression of embryonic neural stem cells and brain size., 2014, 5: 3885.

[31] Zhou ZW, Tapias A, Bruhn C, Gruber R, Sukchev M, Wang ZQ. DNA damage response in microcephaly development of MCPH1 mouse model., 2013, 12(8): 645–655.

[32] Fong KW, Hau SY, Kho YS, Jia Y, He L, Qi RZ. Interaction of CDK5RAP2 with EB1 to track growing microtubule tips and to regulate microtubule dynamics., 2009, 20(16): 3660–3670.

[33] Jiang K, Rezabkova L, Hua SS, Liu Q, Capitani G, Altelaar AFM, Heck AJR, Kammerer RA, Steinmetz MO, Akhmanova A. Microtubule minus-end regulation at spindle poles by an ASPM-katanin complex., 2017, 19(5): 480–492.

[34] Lim NR, Yeap YY, Zhao TT, Yip YY, Wong SC, Xu D, Ang CS, Williamson NA, Xu Z, Bogoyevitch MA, Ng DC. Opposing roles for JNK and aurora a in regulating the association of WDR62 with spindle microtubules., 2015, 128(3): 527–540.

[35] Izraeli S, Lowe LA, Bertness VL, Good DJ, Dorward DW, Kirsch IR, Kuehn MR. The SIL gene is required for mouse embryonic axial development and left-right specification., 1999, 399(6737): 691–694.

[36] Kadir R, Harel T, Markus B, Perez Y, Bakhrat A, Cohen I, Volodarsky M, Feintsein-Linial M, Chervinski E, Zlotogora J, Sivan S, Birnbaum RY, Abdu U, Shalev S, Birk OS. ALFY-Controlled DVL3 autophagy regulates Wnt signaling, determining human brain size., 2016, 12(3): e1005919.

[37] Abdullah U, Farooq M, Mang Y, Marriam Bakhtiar S, Fatima A, Hansen L, Kjaer KW, Larsen LA, Faryal S, Tommerup N, Mahmood Baig S. A novel mutation in CDK5RAP2 gene causes primary microcephaly with speech impairment and sparse eyebrows in a consanguineous pakistani family., 2017, 60(12): 627–630.

[38] Darvish H, Esmaeeli-Nieh S, Monajemi GB, Mohseni M, Ghasemi-Firouzabadi S, Abedini SS, Bahman I, Jamali P, Azimi S, Mojahedi F, Dehghan A, Shafeghati Y, Jankhah A, Falah M, Soltani Banavandi MJ, Ghani M, Garshasbi M, Rakhshani F, Naghavi A, Tzschach A, Neitzel H, Ropers HH, Kuss AW, Behjati F, Kahrizi K, Najmabadi H. A clinical and molecular genetic study of 112 Iranian families with primary microcephaly., 2010, 47(12): 823–828.

[39] Shen J, Eyaid W, Mochida GH, Al-Moayyad F, Bodell A, Woods CG, Walsh CA. ASPM mutations identified in patients with primary microcephaly and seizures., 2005, 42(9): 725–729.

[40] Miyamoto T, Akutsu SN, Fukumitsu A, Morino H, Masatsuna Y, Hosoba K, Kawakami H, Yamamoto T, Shimizu K, Ohashi H, Matsuura S. PLK1-mediated phosphorylation of WDR62/MCPH2 ensures proper mitotic spindle orientation., 2017, 26(22): 4429–4440.

[41] Arroyo M, Kuriyama R, Trimborn M, Keifenheim D, Ca?uelo A, Sánchez A, Clarke DJ, Marchal JA. MCPH1, mutated in primary microcephaly, is required for efficient chromosome alignment during mitosis., 2017, 7(1): 13019.

[42] Issa L, Mueller K, Seufert K, Kraemer N, Rosenkotter H, Ninnemann O, Buob M, Kaindl AM, Morris-Rosendahl DJ. Clinical and cellular features in patients with primary autosomal recessive microcephaly and a novel CDK5RAP2 mutation., 2013, 8: 59.

[43] Guernsey DL, Jiang HY, Hussin J, Arnold M, Bouyakdan K, Perry S, Babineau-Sturk T, Beis J, Dumas N, Evans SC, Ferguson M, Matsuoka M, Macgillivray C, Nightingale M, Patry L, Rideout AL, Thomas A, Orr A, Hoffmann I, Michaud JL, Awadalla P, Meek DC, Ludman M, Samuels ME. Mutations in centrosomal protein CEP152 in primary microcephaly families linked to MCPH4., 2010, 87(1): 40–51.

[44] Hussain MS, Baig SM, Neumann S, Nürnberg G, Farooq M, Ahmad I, Alef T, Hennies HC, Technau M, Altmüller J, Frommolt P, Thiele H, Noegel AA, Nürnberg P. A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function., 2012, 90(5): 871–878.

[45] Omer Javed A, Li Y, Muffat J, Su KC, Cohen MA, Lungjangwa T, Aubourg P, Cheeseman IM, Jaenisch R. Microcephaly modeling of kinetochore mutation reveals a brain-specific phenotype., 2018, 25(2): 368– 382.e5.

[46] Pulvers JN, Bryk J, Fish JL, Wilsch-Br?uninger M, Arai Y, Schreier D, Naumann R, Helppi J, Habermann B, Vogt J, Nitsch R, Tóth A, Enard W, P??bo S, Huttner WB. Mutations in mouse Aspm (abnormal spindle-like microcephaly associated) cause not only microcephaly but also major defects in the germline., 2010, 107(38): 16595–16600.

[47] Marjanovi? M, Sánchez-Huertas C, TerréB, Gómez R, Scheel JF, Pacheco S, Knobel PA, Martínez-Marchal A, Aivio S, Palenzuela L, Wolfrum U, McKinnon PJ, Suja JA, Roig I, Costanzo V, Lüders J, Stracker TH. CEP63 deficiency promotes p53-dependent microcephaly and reveals a role for the centrosome in meiotic recombination., 2015, 6: 7676.

[48] Zhou Y, Qin Y, Qin Y, Xu B, Guo T, Ke HN, Chen M, Zhang L, Han F, Li Y, Chen M, Behrens A, Wang Y, Xu Z, Chen ZJ, Gao F. Wdr62 is involved in female meiotic initiation via activating JNK signaling and associated with POI in humans., 2018, 14(8): e1007463.

[49] Zaqout S, Bessa P, Kr?mer N, Stoltenburg-Didinger G, Kaindl AM. CDK5RAP2 is required to maintain the germ cell pool during embryonic development., 2017, 8(2): 198–204.

[50] Chen J, Ingham N, Clare S, Raisen C, Vancollie VE, Ismail O, McIntyre RE, Tsang SH, Mahajan VB, Dougan G, Adams DJ, White JK, Steel KP. Mcph1-deficient mice reveal a role for MCPH1 in otitis media., 2013, 8(3): e58156.

[51] Ke Q, Li W, Lai X, Chen H, Huang L, Kang Z, Li K, Ren J, Lin X, Zheng H, Huang W, Ma Y, Xu D, Chen Z, Song X, Lin X, Zhuang M, Wang T, Zhuang F, Xi J, Mao FF, Xia H, Lahn BT, Zhou Q, Yang S, Xiang AP. TALEN-based generation of a cynomolgus monkey disease model for human microcephaly., 2016, 26(9): 1048–1061.

[52] Johnson MB, Sun X, Kodani A, Borges-Monroy R, Girskis KM, Ryu SC, Wang PP, Patel K, Gonzalez DM, Woo YM, Yan Z, Liang B, Smith RS, Chatterjee M, Coman D, Papademetris X, Staib LH, Hyder F, Mandeville JB, Grant PE, Im K, Kwak H, Engelhardt JF, Walsh CA, Bae BI. Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size., 2018, 556(7701): 370–375.

[53] Gruber R, Zhou ZW, Sukchev M, Joerss T, Frappart PO, Wang ZQ. MCPH1 regulates the neuroprogenitor division mode by coupling the centrosomal cycle with mitotic entry through the Chk1-Cdc25 pathway., 2011, 13(11): 1325–1334.

[54] Sgourdou P, Mishra-Gorur K, Saotome I, Henagariu O, Tuysuz B, Campos C, Ishigame K, Giannikou K, Quon JL, Sestan N, Caglayan AO, Gunel M, Louvi A. Disruptions in asymmetric centrosome inheritance and WDR62-Aurora kinase B interactions in primary microcephaly., 2017, 7: 43708.

[55] Ramdas Nair A, Singh P, G Salvador arcia D, Rodriguez- Crespo D, Egger B, Cabernard C. The Microcephaly- Associated protein Wdr62/CG7337 Is required to maintain centrosome asymmetry in drosophila neuroblasts., 2016, 14(5): 1100–1113.

[56] Lim NR, Shohayeb B, Zaytseva O, Mitchell N, Millard SS, Ng DCH, Quinn LM. Glial-Specific functions of microcephaly protein WDR62 and interaction with the mitotic kinase AURKA are essential for drosophila brain growth., 2017, 9(1): 32–41.

[57] Novorol C, Burkhardt J, Wood KJ, Iqbal A, Roque C, Coutts N, Almeida AD, He J, Wilkinson CJ, Harris WA. Microcephaly models in the developing zebrafish retinal neuroepithelium point to an underlying defect in metaphase progression., 2013, 3(10): 130065.

[58] Barrera JA, Kao LR, Hammer RE, Seemann J, Fuchs JL, Megraw TL. CDK5RAP2 regulates centriole engagement and cohesion in mice., 2010, 18(6): 913–926.

[59] Capecchi MR, Pozner A. ASPM regulates symmetric stem cell division by tuning cyclin E ubiquitination., 2015, 6: 8763.

[60] Fujimori A, Itoh K, Goto S, Hirakawa H, Wang B, Kokubo T, Kito S, Tsukamoto S, Fushiki S. Disruption of Aspm causes microcephaly with abnormal neuronal differentiation., 2014, 36(8): 661–669.

[61] McIntyre RE, Lakshminarasimhan Chavali P, Ismail O, Carragher DM, Sanchez-Andrade G, Forment JV, Fu B, Del Castillo Velasco-Herrera M, Edwards A, van der Weyden L, Yang F, Sanger Mouse Genetics Project, Ramirez-Solis R, Estabel J, Gallagher FA, Logan DW, Arends MJ, Tsang SH, Mahajan VB, Scudamore CL, White JK, Jackson SP, Gergely F, Adams DJ. Disruption of mouse cenpj, a regulator of centriole biogenesis, phenocopies seckel syndrome., 2012, 8(11): e1003022.

[62] Insolera R, Bazzi H, Shao W, Anderson KV, Shi SH. Cortical neurogenesis in the absence of centrioles., 2014, 17(11): 1528–1535.

[63] Roque H, Wainman A, Richens J, Kozyrska K, Franz A, Raff JW.Cep135/Bld10 maintains proper centriole structure but is dispensable for cartwheel formation, 2012, 125(Pt 23): 5881–5886.

[64] Yang YJ, Baltus AE, Mathew RS, Murphy EA, Evrony GD, Gonzalez DM, Wang EP, Marshall-Walker CA, Barry BJ, Murn J, Tatarakis A, Mahajan MA, Samuels HH, Shi Y, Golden JA, Mahajnah M, Shenhav R, Walsh CA. Microcephaly gene links trithorax and REST/NRSF to control neural stem cell proliferation and differentiation., 2012, 151(5): 1097–1112.

[65] Hilbert M, Noga A, Frey D, Hamel V, Guichard P, Kraatz SH, Pfreundschuh M, Hosner S, Flückiger I, Jaussi R, Wieser MM, Thieltges KM, Deupi X, Müller DJ, Kammerer RA, G?nczy P, Hirono M, Steinmetz MO. SAS-6 engineering reveals interdependence between cartwheel and microtubules in determining centriole architecture., 2016, 18(4): 393–403.

[66] Yamamoto S, Jaiswal M, Charng WL, Gambin T, Karaca E, Mirzaa G, Wiszniewski W, Sandoval H, Haelterman NA, Xiong B, Zhang K, Bayat V, David G, Li T, Chen K, Gala U, Harel T, Pehlivan D, Penney S, Vissers LELM, de Ligt J, Jhangiani SN, Xie YJ, Tsang SH, Parman Y, Sivaci M, Battaloglu E, Muzny D, Wan YW, Liu Z, Lin-Moore AT, Clark RD, Curry CJ, Link N, Schulze KL, Boerwinkle E, Dobyns WB, Allikmets R, Gibbs RA, Chen R, Lupski JR, Wangler MF, Bellen HJ. A drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases., 2014, 159(1): 200–214.

[67] Bianchi FT, Tocco C, Pallavicini G, Liu Y, VernìF(xiàn), Merigliano C, Bonaccorsi S, El-Assawy N, Priano L, Gai M, Berto GE, Chiotto AM, SgròF, Caramello A, Tasca L, Ala U, Neri F, Oliviero S, Mauro A, Geley S, Gatti M, Di Cunto F. Citron kinase deficiency leads to chromosomal instability and TP53-Sensitive microcephaly., 2017, 18(7): 1674–1686.

[68] DiStasio A, Driver A, Sund K, Donlin M, Muraleedharan RM, Pooya S, Kline-Fath B, Kaufman KM, Prows CA, Schorry E, Dasgupta B, Stottmann RW. Copb2 is essential for embryogenesis and hypomorphic mutations cause human microcephaly., 2017, 26(24): 4836–4848.

[69] Fujikura K, Setsu T, Tanigaki K, Abe T, Kiyonari H, Terashima T, Sakisaka T. Kif14 mutation causes severe brain malformation and hypomyelination., 2013, 8(1): e53490.

[70] Perez Y, Bar-Yaacov R, Kadir R, Wormser O, Shelef I, Birk OS, Flusser H, Birnbaum RY. Mutations in the microtubule-associated protein MAP11 (C7orf43) cause microcephaly in humans and zebrafish., 2019, 142(3): 574–585.

[71] Yang SZ, Lin FT, Lin WC. MCPH1/BRIT1 cooperates with E2F1 in the activation of checkpoint, DNA repair and apoptosis., 2008, 9(9): 907–915.

[72] Xu D, Yao M, Wang Y, Yuan L, Hoeck JD, Yu J, Liu L, Yeap YYC, Zhang W, Zhang F, Feng Y, Ma T, Wang Y, Ng DCH, Niu X, Su B, Behrens A, Xu Z. MEKK3 coordinates with FBW7 to regulate WDR62 stability and neurogenesis., 2018, 16(12): e2006613.

[73] Luo X, Liu Y, Feng W, Lei L, Du Y, Wu J, Wang S. NUP37, a positive regulator of YAP/TEAD signaling, promotes the progression of hepatocellular carcinoma., 2017, 8(58): 98004–98013.

[74] Clark DA, Mitra PP, Wang SS. Scalable architecture in mammalian brains., 2001, 411(6834): 189–193.

[75] Rakic P. A small step for the cell, a giant leap for mankind: a hypothesis of neocortical expansion during evolution., 1995, 18(9): 383–388.

[76] Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, Homfray T, Penninger JM, Jackson AP, Knoblich JA. Cerebral organoids model human brain development and microcephaly., 2013, 501(7467): 373–379.

[77] Gabriel E, Wason A, Ramani A, Gooi LM, Keller P, Pozniakovsky A, Poser I, Noack F, Telugu NS, Calegari F, ?ari? T, Hescheler J, Hyman AA, Gottardo M, Callaini G, Alkuraya FS, Gopalakrishnan J. CPAP promotes timely cilium disassembly to maintain neural progenitor pool., 2016, 35(8): 803–819.

[78] Gabriel E, Gopalakrishnan J. Generation of iPSC-derived human brain organoids to model early neurodevelopmental disorders., 2017, (122).

[79] Bartholomeusz HH, Courchesne E, Karns CM. Relationship between head circumference and brain volume in healthy normal toddlers, children, and adults., 2002, 33(5): 239–241.

[80] Pavone P, Praticò AD, Rizzo R, Corsello G, Ruggieri M, Parano E, Falsaperla R. A clinical review on megalencephaly: a large brain as a possible sign of cerebral impairment., 2017, 96(26): e6814.

[81] Courchesne E, Carper R, Akshoomoff N. Evidence of brain overgrowth in the first year of life in autism., 2003, 290(3): 337–344.

[82] Courchesne E. Brain development in autism: early overgrowth followed by premature arrest of growth., 2004, 10(2): 106–111.

[83] Klein S, Sharifi-Hannauer P, Martinez-Agosto JA. Macrocephaly as a clinical indicator of genetic subtypes in autism., 2013, 6(1): 51–56.

Update on autosomal recessive primary microcephaly (MCPH)-associated proteins

Yujie Wang, Xiaokun Zhou, Dan Xu

Brain development diseases refer to a group of diseases that affect the development of the brain or the central nervous system. Autosomal recessive primary microcephaly (MCPH) is a typical neurodevelopmental disorder characterized by a decreased brain size, mental retardation and abnormal behaviors. To date, at least 25 genes have been discovered to cause MCPH when mutated. These genes were namedaccording to the discovery order. MCPH proteins play important roles in regulating brain developmental signaling pathways. Here, we provide a timely review of the expression patterns, cellular localization, molecular functions, phenotypes, as well as animal models of these 25 MCPH proteins that will expedite our understanding of the pathogenesis of brain disorders at both molecular and cellular levels.

microcephaly; expression pattern; cellular component; phenotype overview; molecular function; animal models

2019-04-18；

2019-05-15

福建省自然科學(xué)基金項(xiàng)目（編號(hào)：2018J01730）資助[Supported by the Natural Science Foundation of the Fujian Province (No. 2018J01730)]

王玉杰，碩士研究生，專(zhuān)業(yè)方向：細(xì)胞生物學(xué)。E-mail: yjwang9412@163.com

徐丹，博士，助理研究員，研究方向：腦發(fā)育相關(guān)疾病。E-mail: xu200828@163.com

10.16288/j.yczz.19-070

2019/6/11 17:00:20

URI: http://kns.cnki.net/kcms/detail/11.1913.R.20190611.1700.001.html

(責(zé)任編委: 許執(zhí)恒)