MicroRNA調(diào)控耳蝸毛細(xì)胞發(fā)育的分子機(jī)制

饒琳，孟飛龍，房冉，蔡晨依，趙小立

MicroRNA調(diào)控耳蝸毛細(xì)胞發(fā)育的分子機(jī)制

饒琳，孟飛龍，房冉，蔡晨依，趙小立

浙江大學(xué)生命科學(xué)學(xué)院遺傳與再生生物學(xué)研究所，浙江省細(xì)胞與基因工程重點(diǎn)研究實(shí)驗(yàn)室，杭州 310058

耳聾是嚴(yán)重影響人類生活質(zhì)量的全球重大健康問(wèn)題之一。目前，因耳蝸毛細(xì)胞損傷而導(dǎo)致的耳聾疾病尚未有成功的治療方法。MicroRNA (miRNA)作為一類高度保守的內(nèi)源性非編碼小RNA，在耳蝸以及毛細(xì)胞發(fā)育過(guò)程中發(fā)揮著重要作用。本文介紹了miRNA在耳蝸毛細(xì)胞產(chǎn)生過(guò)程中的時(shí)空表達(dá)，揭示了其不可或缺的重要作用；同時(shí)闡述了miRNA參與調(diào)控耳蝸毛細(xì)胞發(fā)育中相關(guān)轉(zhuǎn)錄因子的分子機(jī)制，為耳聾的毛細(xì)胞移植治療和毛細(xì)胞再生研究提供理論參考。

miRNA；耳蝸；聽(tīng)力損失；毛細(xì)胞

miRNA是一類高度保守的內(nèi)源性非編碼小RNA，通過(guò)抑制mRNA轉(zhuǎn)錄負(fù)調(diào)控靶基因的表達(dá)水平，從而參與調(diào)控細(xì)胞的生長(zhǎng)發(fā)育、細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)、增殖分化、細(xì)胞凋亡、脂類代謝、蛋白質(zhì)降解等過(guò)程[1]。1993年，在秀麗隱桿線蟲(chóng)()中最早發(fā)現(xiàn)miRNA基因lin-4[2]。它與lin-14 mRNA 3?-UTR的堿基序列部分互補(bǔ)，通過(guò)降解靶基因lin-14參與調(diào)控線蟲(chóng)的生長(zhǎng)發(fā)育[3]。隨后越來(lái)越多的miRNA在植物、無(wú)脊椎動(dòng)物和脊椎動(dòng)物的組織中被發(fā)現(xiàn)[4]。近幾年的研究發(fā)現(xiàn)miRNA在動(dòng)物耳蝸的各類細(xì)胞中表達(dá)豐富[5]，已有研究表明miR-183家族在內(nèi)耳毛細(xì)胞發(fā)育功能的調(diào)控中發(fā)揮了重要作用[6]。本文歸納總結(jié)了耳蝸毛細(xì)胞中主要miRNA的詳細(xì)表達(dá)分布情況，并以miR-183家族的3個(gè)成員miR-96、miR-182和miR-183為主，分別闡述miRNA在內(nèi)耳中的時(shí)空表達(dá)以及在內(nèi)耳和毛細(xì)胞發(fā)育過(guò)程中參與調(diào)控的相關(guān)機(jī)制，旨在為進(jìn)一步探索內(nèi)耳毛細(xì)胞的發(fā)育分化、體外誘導(dǎo)及原位再生提供理論依據(jù)。

1 耳蝸中各類型細(xì)胞表達(dá)的miRNA

1.1 內(nèi)耳的結(jié)構(gòu)與功能

哺乳動(dòng)物的耳是由外耳、中耳和內(nèi)耳3個(gè)部分組成，內(nèi)耳由負(fù)責(zé)感受聲音的耳蝸和感受位置及運(yùn)動(dòng)覺(jué)的前庭器官組成[7]。耳蝸螺旋器(Corti器)坐落在基膜上，由感覺(jué)上皮(毛細(xì)胞)和支持細(xì)胞以及其他一些附屬結(jié)構(gòu)組成[8]。Corti器有3排外毛細(xì)胞(outer hair cell)和1排內(nèi)毛細(xì)胞(inner ear hair cells)[9]。外毛細(xì)胞被稱為“耳蝸放大器”，增強(qiáng)感覺(jué)上皮細(xì)胞對(duì)不同聲音頻率的響應(yīng)能力，形成“機(jī)械—電—機(jī)械”的正反饋環(huán)路[10]。內(nèi)毛細(xì)胞受到聲音刺激，纖毛向外側(cè)擺動(dòng)，觸發(fā)神經(jīng)遞質(zhì)谷氨酸的釋放，促使聽(tīng)神經(jīng)傳入沖動(dòng)產(chǎn)生。聲音沖動(dòng)穿過(guò)傳入神經(jīng)到達(dá)耳蝸螺旋神經(jīng)節(jié)(spiral ganglion)，進(jìn)一步傳到聽(tīng)覺(jué)中樞，傳達(dá)到大腦產(chǎn)生聽(tīng)覺(jué)[11]。耳蝸膜性結(jié)構(gòu)包括基膜、前庭膜和蓋膜3個(gè)部分?；な巧掀そM織基底面與深部結(jié)締組織之間的一層薄膜，給耳蝸部分提供韌性和質(zhì)量，基膜與耳蝸螺旋韌帶的蝸管相連形成一定的功能聯(lián)系[12]。前庭膜起始于蝸軸側(cè)的螺旋緣，與基底膜成45°，由兩層細(xì)胞組成的一層薄膜，該膜可調(diào)節(jié)離子和液體平衡的作用[13]。

1.2 miRNA在耳蝸中的表達(dá)

miRNA與聽(tīng)覺(jué)功能密切相關(guān)，在耳蝸各類型的細(xì)胞中已經(jīng)檢測(cè)出超過(guò)100種miRNA[14]，如miR- 183、miR-96、miR-182、miR-124、miR-34a、miR-376和miR-135b等[15]。其中，miR-96、miR-182和miR-183等在小鼠和人的基因組中成簇排列，并且都是朝向同一方向轉(zhuǎn)錄生成，所以將這3種miRNA統(tǒng)稱為miR-183基因簇或miR-183家族[16]。在毛細(xì)胞和螺旋神經(jīng)節(jié)中的miRNA種類較多，已被證實(shí)的有miR-183家族、miR-15a、miR-30b、miR-99a、miR-18a、miR-140和miR-194等[17]。在內(nèi)螺旋溝也檢測(cè)到miR-96、miR-182和miR-183共3個(gè)miRNA，而在螺旋緣除了檢測(cè)到miR-183家族的3個(gè)miRNA成員，還檢測(cè)到miR-205表達(dá)[18]。同時(shí)，miR-205也存在于前庭膜和耳蝸螺旋韌帶上[19]?；ど铣舜嬖趍iR-205a，此外還高表達(dá)miR-15a、miR-30b和miR-99a等miRNA[20]。但是支持細(xì)胞只有miR-15a、miR-30b和miR-99a表達(dá)[21]。邊緣細(xì)胞中存在miR-376a和miR-376b，這些miRNA在內(nèi)耳的其他部位中沒(méi)有檢測(cè)出來(lái)[22]。

除了上述提及的表達(dá)水平較高的miRNA，在已知成熟miRNA中有102種在耳蝸中表達(dá)，占全身miRNA總量的1/3[23]。組成耳蝸的細(xì)胞種類豐富，從miRNA的表達(dá)情況中可以看出一些組織和細(xì)胞存在著相同的miRNA[24]，比如毛細(xì)胞、螺旋神經(jīng)節(jié)、螺旋緣、內(nèi)螺旋溝等組織都有miR-96、miR-182和miR- 183的存在，前庭膜、螺旋緣、耳蝸螺旋韌帶、基膜等組織則都表達(dá)了miR-205a[25]。這些結(jié)果為進(jìn)一步掌握耳蝸的發(fā)育過(guò)程以及不同細(xì)胞組織之間的協(xié)同作用提供了研究依據(jù)[26]。在耳蝸中不同細(xì)胞和組織中主要高度表達(dá)的miRNA的表達(dá)情況如圖1所示。

2 miRNA在耳蝸發(fā)育過(guò)程中的時(shí)空表達(dá)

2.1 內(nèi)耳的發(fā)育過(guò)程

脊椎動(dòng)物的內(nèi)耳發(fā)育起源于胚胎的外胚層[27]。聽(tīng)泡(otic vesicle)又稱耳囊(otic capsule)，起源于外胚層的聽(tīng)基板，在外胚層表面接近于神經(jīng)板[28]。內(nèi)耳的始基聽(tīng)泡發(fā)育產(chǎn)生于小鼠胚胎第8天(embryonic day 8, E8)至第11天，而人類在胚胎第4周末期才發(fā)育產(chǎn)生聽(tīng)泡[29]。在此發(fā)育階段，內(nèi)耳的平衡和聽(tīng)覺(jué)神經(jīng)節(jié)也開(kāi)始發(fā)育，該神經(jīng)節(jié)是由內(nèi)耳原始聽(tīng)泡的前腹內(nèi)側(cè)細(xì)胞從聽(tīng)泡分離并融合形成[30]。小鼠在E10.5~E14開(kāi)始形成前庭和耳蝸，聽(tīng)泡脫離表面外胚層沉降到下方間充質(zhì)內(nèi)形成了聽(tīng)囊，聽(tīng)囊背側(cè)發(fā)育為前庭部，而聽(tīng)囊腹側(cè)發(fā)育為耳蝸部[31]。而感覺(jué)細(xì)胞的分化期，小鼠約在E13~E19，耳蝸上皮逐漸分化為感覺(jué)上皮，已有可分辨出的支持細(xì)胞和毛細(xì)胞[32]。出生時(shí)，前庭感覺(jué)器官發(fā)育已經(jīng)接近于成熟，耳蝸已成型但體積比成熟期的耳蝸小[33]。出生后，前庭感覺(jué)器官、耳蝸逐漸發(fā)育成熟[34]，小鼠出生后第30天(postnatal day 30, P30)左右內(nèi)耳器官完全發(fā)育成熟[35]。

圖1 miRNA在耳蝸各類細(xì)胞中的表達(dá)

2.2 miRNA在動(dòng)物模型耳蝸中的時(shí)空表達(dá)

miRNAs的表達(dá)呈現(xiàn)時(shí)間、空間及組織細(xì)胞的特異性[36]，表明其參與了組織的形態(tài)形成和細(xì)胞分化的過(guò)程[37]。由于人類的耳蝸組織不易獲取，關(guān)于耳蝸miRNA的時(shí)空表達(dá)研究多局限于模式生物，再利用外推法來(lái)理解其在人類耳蝸中的具體功能[38]。在耳蝸領(lǐng)域最早進(jìn)行研究的動(dòng)物模型是小鼠，通過(guò)表達(dá)譜芯片分析小鼠耳蝸發(fā)育過(guò)程中不同時(shí)間點(diǎn)miRNA表達(dá)的狀況[39]。在小鼠胚胎的整個(gè)發(fā)育過(guò)程中，miR-183和miR-182最早在胚胎期E9.5于聽(tīng)泡中表達(dá)。隨著內(nèi)耳在胚胎期的進(jìn)一步發(fā)育，miR-183家族的3個(gè)成員在E11.5時(shí)出現(xiàn)表達(dá)差異，miR-182只有miR-182-5p表達(dá)，而在E12時(shí)miR-96、miR-182和miR-183呈現(xiàn)無(wú)差異表達(dá)，這可能反映了不同種類miRNA在內(nèi)耳發(fā)育中的微小差異[40]。胚胎發(fā)育前期在miR-96、miR-182、miR-183聽(tīng)囊和螺旋神經(jīng)節(jié)均有表達(dá)，E17.5時(shí)開(kāi)始僅在毛細(xì)胞及其神經(jīng)元中表達(dá)[41]。出生時(shí)(P0)，耳蝸毛細(xì)胞中檢測(cè)到了miR-183家族、miR-15a*、miR-18a*、miR-30a*、miR-99a*、miR-199a*、miR-200*等諸多miRNAs的表達(dá)[42]。其中miR-183家族在小鼠出生后4-5天還存在于感覺(jué)前體細(xì)胞中，隨后集中在耳蝸毛細(xì)胞呈現(xiàn)高度表達(dá)狀態(tài)[43]。在P30時(shí)小鼠耳蝸已完全發(fā)育，此時(shí)在毛細(xì)胞中仍然可以檢測(cè)到miR-183家族的表達(dá)[44]。從新生小鼠的耳蝸檢測(cè)出的miRNA表達(dá)譜開(kāi)始，經(jīng)過(guò)聽(tīng)覺(jué)功能的發(fā)育和成熟，miRNA并沒(méi)有發(fā)生實(shí)質(zhì)性的改變，這表明miRNA的表達(dá)在很大程度上是在胚胎發(fā)育過(guò)程中建立起來(lái)的。從耳蝸發(fā)育的整個(gè)過(guò)程上看，miR-183、miR-96和miR-182的表達(dá)呈現(xiàn)出了時(shí)空組織的特異性，這種時(shí)間和空間上的表達(dá)與耳蝸的功能成熟密切相關(guān)[45]。miRNA家族時(shí)空表達(dá)的特異性見(jiàn)圖2所示。

3 miR-183家族與毛細(xì)胞發(fā)育

3.1 毛細(xì)胞概述

人類內(nèi)耳約有15 000個(gè)毛細(xì)胞，其中作為聽(tīng)覺(jué)感受器的耳蝸毛細(xì)胞約有3000個(gè)[46]。耳蝸毛細(xì)胞是分化成熟、高度特異性的終末細(xì)胞，哺乳動(dòng)物毛細(xì)胞在出生后再生能力非常有限，聽(tīng)覺(jué)毛細(xì)胞損傷后很難分化形成新的毛細(xì)胞[47]。遺傳或者獲得性因素如年齡增長(zhǎng)、耳毒性藥物、病毒感染、噪音和外傷等都會(huì)使毛細(xì)胞受到損傷[48]，從而造成感音神經(jīng)性耳聾(sensorineural hearing loss, SNHL)[49]。長(zhǎng)期以來(lái)，感音神經(jīng)性耳聾患者改善聽(tīng)力的選擇僅僅限于助聽(tīng)器、人工耳蝸等設(shè)備，但這些方法無(wú)法從根本上解決問(wèn)題[50]。因此，研究毛細(xì)胞的發(fā)育和再生的機(jī)制，可用于指導(dǎo)體外誘導(dǎo)干細(xì)胞分化為類毛細(xì)胞的研究，并通過(guò)細(xì)胞移植替換受損毛細(xì)胞，為治療耳聾疾病帶來(lái)新曙光[51]。

3.2 miR-183家族

目前在耳蝸毛細(xì)胞的miRNA研究中，miR-183家族的研究比較深入[52]。這個(gè)家族在進(jìn)化過(guò)程中具有高度保守性，在結(jié)構(gòu)上具有高度同源性(圖3)。miR-183和miR-96之間有約1 kb的間隔區(qū)，miR-96和miR-182之間有約2.7~3.5 kb的間隔區(qū)。盡管3者之間的序列具有高度的相似性，但是其中微小的序列差異導(dǎo)致它們擁有不同的mRNA靶標(biāo)。miR-183家族是最先被報(bào)道參與了纖毛化的感覺(jué)上皮細(xì)胞和神經(jīng)纖毛細(xì)胞的器官發(fā)生和發(fā)育功能的基因簇[53]，它們?cè)谀承┢鞴偃缪劬Α⒈亲雍蛢?nèi)耳中有特殊的表達(dá)，對(duì)動(dòng)物感覺(jué)器官的發(fā)育和功能的形成至關(guān)重要[54]。

3.2.1 miR-96

miR-96首先在人類癌細(xì)胞中被檢測(cè)到，是miR-183家族中第一個(gè)被發(fā)現(xiàn)的miRNA成員[55]。miR-96是一種感覺(jué)器官特異性的miRNA，在哺乳動(dòng)物耳蝸發(fā)育期間表達(dá)，可導(dǎo)致、和等重要發(fā)育基因表達(dá)下調(diào)。miR-96的種子區(qū)域的點(diǎn)突變會(huì)引起DNA序列多態(tài)性，導(dǎo)致人和小鼠常染色體顯性非綜合征性耳聾(non-syndromic hearing loss, NSHL)[56]。miR-96的種子序列第4個(gè)堿基G>A的突變，是第一個(gè)被發(fā)現(xiàn)的與遺傳性耳聾相關(guān)的miRNA突變。Mencia等[57]從遺傳性耳聾家系中證實(shí)+13G>A和+14C>A兩個(gè)種子區(qū)域點(diǎn)突變也會(huì)影響成熟的miR-96與靶基因的結(jié)合效率，從而導(dǎo)致其對(duì)耳蝸毛細(xì)胞的調(diào)節(jié)失衡，最終引起了耳聾產(chǎn)生。Lewis等[58]利用強(qiáng)致癌劑N-亞硝基-N-乙基脲(N-ethyl-N-nitro-sourea, ENU)致小鼠聽(tīng)力損失，進(jìn)一步對(duì)miR-96的種子區(qū)域點(diǎn)突變進(jìn)行研究，發(fā)現(xiàn)有的突變體小鼠完全聽(tīng)力喪失并且毛細(xì)胞纖毛束不規(guī)則。Kuhn等[59]利用ENU小鼠突變體來(lái)探索miR-96在聽(tīng)覺(jué)器官發(fā)育至成熟過(guò)程中的作用機(jī)制，發(fā)現(xiàn)miR-96種子區(qū)域的突變影響了、和等內(nèi)耳毛細(xì)胞相關(guān)靶基因的正常表達(dá)，毛細(xì)胞靜纖毛束的成熟和耳蝸內(nèi)聽(tīng)覺(jué)神經(jīng)連接的重塑都會(huì)受到影響，進(jìn)一步闡明了這一種子區(qū)域與聽(tīng)力損失有關(guān)[60]，miR-96可能與內(nèi)耳毛細(xì)胞的靜纖毛束的成熟和耳蝸神經(jīng)的發(fā)育密切聯(lián)系[61]。因此，了解miR-96的作用機(jī)制有助于進(jìn)一步解釋維持耳蝸正?；顒?dòng)所需基因的有序表達(dá)，并有助于深入研究非綜合征性聾病發(fā)生的機(jī)制[62]。

圖2 miR-183家族在小鼠耳蝸發(fā)育過(guò)程中表達(dá)的時(shí)間圖

E為胚胎期，P為出生后。

圖3 miR-183家族基因簇在人和小鼠中的染色體位置及種子序列

紅色部分為microRNA種子系列。

3.2.2 miR-182

miR-182活性可能與靶基因有關(guān)，是一種參與毛細(xì)胞發(fā)育和分化的轉(zhuǎn)錄因子[63]。順鉑(cisplatin, CDDP)誘導(dǎo)的毛細(xì)胞凋亡前過(guò)表達(dá)miR-182，可抑制內(nèi)源性凋亡途徑的3個(gè)關(guān)鍵基因、和，從而保護(hù)耳蝸毛細(xì)胞免于細(xì)胞凋亡[64]。miR-182過(guò)表達(dá)會(huì)導(dǎo)致耳蝸毛細(xì)胞數(shù)量增加，在支持細(xì)胞中miR-182的低表達(dá)可抑制該細(xì)胞轉(zhuǎn)分化為毛細(xì)胞。因此，在感覺(jué)細(xì)胞中過(guò)表達(dá)miR-182可以促進(jìn)毛細(xì)胞再生，有望治療由毛細(xì)胞丟失引起的感音神經(jīng)性耳聾。Hildebrand等[65]利用隱性常染色體非綜合征性耳聾人類家系，在()基因的3?-UTR中發(fā)現(xiàn)了miR-182結(jié)合位點(diǎn)的C>A的純合子突變。Wang等[66]將小鼠耳蝸干/祖細(xì)胞進(jìn)行體外培養(yǎng)，發(fā)現(xiàn)過(guò)表達(dá)miR-182促進(jìn)耳蝸干/祖細(xì)胞分化成毛細(xì)胞，此外，miR-182還與神經(jīng)感覺(jué)器官、視覺(jué)感覺(jué)器官等器官的發(fā)育調(diào)控有關(guān)。在針對(duì)自閉癥的全基因組研究中，Schellenberg等[67]在接近miR-182染色體位點(diǎn)的地方發(fā)現(xiàn)了這種疾病的易感基因，miR-182缺陷會(huì)導(dǎo)致自閉癥的發(fā)生。Xu等[51]體外研究表明是miR-96和miR-182的直接靶點(diǎn)，是建立和維持視網(wǎng)膜發(fā)育和維持所必需的轉(zhuǎn)錄因子，miR-182的異常導(dǎo)致感覺(jué)器官發(fā)育程序的缺陷。

3.2.3 miR-183

miR-183能夠調(diào)控耳蝸內(nèi)毛細(xì)胞的發(fā)育分化及成熟的生理過(guò)程，miR-183可通過(guò)負(fù)調(diào)控其下游靶基因，使毛細(xì)胞的細(xì)胞骨架發(fā)生改變[68]。內(nèi)耳在暴露于噪聲28 d后miR-183、miR-96和miR-182的表達(dá)水平降低, 這與噪聲導(dǎo)致外毛細(xì)胞的減少有關(guān)。在強(qiáng)烈的噪聲刺激導(dǎo)致耳蝸毛細(xì)胞損傷后，miR-183可以通過(guò)抑制的表達(dá)來(lái)保護(hù)強(qiáng)刺激后受到損傷的耳蝸[69]。在體外培養(yǎng)的耳蝸螺旋器中，用嗎啡反義寡核苷酸抑制miR-183的表達(dá)可導(dǎo)致Taok1蛋白增加并伴隨耳蝸毛細(xì)胞的凋亡，說(shuō)明miR-183在調(diào)節(jié)聽(tīng)覺(jué)創(chuàng)傷的耳蝸反應(yīng)方面具有潛在的作用。Kim等[70]發(fā)現(xiàn)在新霉素誘導(dǎo)耳毒性斑馬魚中抑制miR-183表達(dá)，會(huì)降低毛細(xì)胞的再生，反之在斑馬魚胚胎中人工注射miR-183可以促進(jìn)毛細(xì)胞正常發(fā)育。miR-183表達(dá)的變化先于動(dòng)物形態(tài)學(xué)和功能的變化，在小鼠耳蝸發(fā)育的過(guò)程中，促進(jìn)細(xì)胞增殖和分化的miR-183呈上調(diào)趨勢(shì)，而在小鼠衰老時(shí)miR-183下調(diào)，促凋亡通路的調(diào)控因子miR-29家族和miR-34家族成員上調(diào)。

4 miRNA調(diào)控耳蝸發(fā)育的分子機(jī)制

4.1 miRNA與靶基因

人們對(duì)miRNA如何控制耳蝸發(fā)育的理解始于對(duì)突變體動(dòng)物的研究。在斑馬魚模型中，幼體突變體的聽(tīng)覺(jué)器官嚴(yán)重畸形[71]。在小鼠中，基因在耳部早期發(fā)育時(shí)缺失，會(huì)導(dǎo)致內(nèi)耳的整體尺寸減小，耳蝸生長(zhǎng)受到嚴(yán)重阻礙[72]?；蛟趐re-miRNA加工成為成熟miRNA過(guò)程中至關(guān)重要，缺失嚴(yán)重影響了內(nèi)耳的發(fā)育，間接地說(shuō)明了miRNAs對(duì)耳蝸的重要性。miRNAs在耳蝸發(fā)育過(guò)程中參與調(diào)控重要基因的表達(dá)水平，從而參與了調(diào)控耳蝸細(xì)胞的增殖、遷移、發(fā)育和凋亡等過(guò)程。作為感覺(jué)前體細(xì)胞區(qū)域較早出現(xiàn)的標(biāo)志之一，在人類耳蝸發(fā)育過(guò)程中的缺失引起了感音神經(jīng)性耳聾，是內(nèi)耳發(fā)育和毛細(xì)胞命運(yùn)有關(guān)的轉(zhuǎn)錄因子，miR-182參與了靶基因和的表達(dá)調(diào)控[66]。miR-96的靶基因是和，其中是毛細(xì)胞成熟的重要基因[59]。此外，miR-96的靶基因還包括了漸進(jìn)性耳聾的2個(gè)關(guān)鍵基因(表皮生長(zhǎng)因子受體)和(神經(jīng)營(yíng)養(yǎng)因子受體)[55]。在其3'-UTR中包含一個(gè)高度保守的miR-96/-182結(jié)合位點(diǎn),被認(rèn)為是miR-96和miR-182的共同靶基因。Gu等[73]研究證實(shí)基因突變小鼠與ENU突變小鼠具有相似的立體纖毛形態(tài)，利用脂質(zhì)體將miR-96和miR-182轉(zhuǎn)染到耳蝸毛細(xì)胞中，可導(dǎo)致在mRNA水平和蛋白水平的表達(dá)量下降，進(jìn)一步研究結(jié)果表明是由miR-96和miR-182直接調(diào)控的，確認(rèn)靶序列位于3?-UTR內(nèi)的核苷760~766 bp之間。miR-183以為靶基因，通過(guò)抑制整合素α3的表達(dá)來(lái)控制耳蝸發(fā)育中的細(xì)胞增殖[71]。

除了上述的miR-183家族參與耳蝸發(fā)育的重要靶基因的調(diào)控，其他miRNA也在耳蝸發(fā)育過(guò)程中發(fā)揮重要作用。是負(fù)責(zé)產(chǎn)生透明軟骨組分的基因，miR-9是的調(diào)控因子[72]。miR-124在耳蝸中的靶基因是Wnt信號(hào)通路的兩個(gè)抑制因子和。miR-124于耳囊的神經(jīng)上皮中高水平表達(dá)，促進(jìn)神經(jīng)細(xì)胞分化和輪廓形成[74]。miR-135b調(diào)控耳蝸中的轉(zhuǎn)錄激活因子[75]miR-194在耳蝸神經(jīng)元和毛細(xì)胞中高度表達(dá)，通過(guò)調(diào)控和基因影響耳蝸神經(jīng)細(xì)胞的分化[76]。內(nèi)耳形態(tài)發(fā)生的關(guān)鍵調(diào)節(jié)因子是miR-200，在耳蝸和前庭上皮細(xì)胞中選擇性表達(dá)，通過(guò)轉(zhuǎn)錄沉默和基因調(diào)控上皮–間質(zhì)轉(zhuǎn)化[77]。磷酸核糖焦磷酸合成酶1(PRPS1)的突變與一系列非綜合征到綜合征性聽(tīng)力損失有關(guān)，表達(dá)水平受miR-376的調(diào)控[78]?？傊?，這些miRNA以及其下游靶基因在耳蝸中組成了復(fù)雜的調(diào)控網(wǎng)絡(luò)，共同調(diào)控耳蝸的發(fā)育過(guò)程[79]。有關(guān)miRNA調(diào)控耳蝸發(fā)育的靶基因見(jiàn)表1。

4.2 miRNA參與的信號(hào)通路

耳蝸前體細(xì)胞在耳蝸分化的過(guò)程中主要產(chǎn)生3種譜系的細(xì)胞，分別是神經(jīng)前體細(xì)胞、感覺(jué)前體細(xì)胞和其它細(xì)胞[88]。神經(jīng)細(xì)胞產(chǎn)生所必需的細(xì)胞因子是和，可以抑制和神經(jīng)元的分化，而miR-182抑制的表達(dá)[89]。感覺(jué)細(xì)胞的產(chǎn)生時(shí)需要和等基因參與調(diào)控，細(xì)胞周期蛋白依賴性激酶(Cyclin-dependent kinase)抑制劑p27kip1，p19Ink4d和Rb抑制感覺(jué)細(xì)胞進(jìn)入細(xì)胞周期，促進(jìn)感覺(jué)前體細(xì)胞分化成毛細(xì)胞和支持細(xì)胞[90]毛細(xì)胞的形成和成熟需要和等細(xì)胞因子的調(diào)控[91]。Wnt信號(hào)通路[92]、Notch信號(hào)通路[93]、Shh信號(hào)通路[94]、FGF信號(hào)通路[95]和TGF信號(hào)通路[96]等信號(hào)通路參與了耳蝸的發(fā)育過(guò)程。其中，經(jīng)典Wnt/β-catenin信號(hào)通路作用于耳蝸發(fā)育的最初階段, 主要負(fù)責(zé)調(diào)控聽(tīng)囊和聽(tīng)基板的特化；而Wnt/PCP信號(hào)通路在哺乳動(dòng)物的毛細(xì)胞靜纖毛的生長(zhǎng)排列和蝸管的延伸過(guò)程中發(fā)揮著重要作用[97]。miR-183家族可以通過(guò)抑制的表達(dá)，調(diào)控Wnt/β-catenin信號(hào)通路的傳導(dǎo)[98]，而糖原合成酶激酶GSK3β通過(guò)Wnt/β-catenin /TCF/LEF-1信號(hào)通路影響miR-183家族的表達(dá)[99]。在哺乳動(dòng)物發(fā)育過(guò)程中，Notch信號(hào)通路參與耳蝸感覺(jué)上皮的發(fā)育與分化過(guò)程，通過(guò)側(cè)向抑制作用調(diào)控耳蝸感覺(jué)前體細(xì)胞向毛細(xì)胞的分化，從而確保內(nèi)毛細(xì)胞至外毛細(xì)胞的正常分化順序[100]。miR-384-5p轉(zhuǎn)染細(xì)胞后，的表達(dá)水平顯著下調(diào)[101]，miR-183通過(guò)抑制基因和從而抑制 Notch信號(hào)通路，參與毛細(xì)胞的分化和再生[102]。在耳蝸發(fā)育的早期階段，F(xiàn)GF信號(hào)通路調(diào)控早期聽(tīng)基板的形成，在耳蝸發(fā)育后期，F(xiàn)GF信號(hào)分子主要參與毛細(xì)胞的發(fā)育，然而miRNA參與FGF信號(hào)通路調(diào)節(jié)的報(bào)道目前尚未見(jiàn)報(bào)道[103]。

表1 miRNA在耳蝸中的靶基因

miRNA在耳蝸發(fā)育過(guò)程中調(diào)節(jié)細(xì)胞凋亡方面還發(fā)揮了重要作用[104]。在電離輻射誘導(dǎo)的毛細(xì)胞死亡模型中，作為促凋亡因子的miR-207通過(guò)靶向基因(是PI3K/AKT途徑等信號(hào)通路的關(guān)鍵基因)發(fā)揮了重要作用[105]。miR-182通過(guò)抑制PI3K AKT信號(hào)通路的直接靶點(diǎn)(促凋亡轉(zhuǎn)錄因子)的翻譯來(lái)抑制細(xì)胞凋亡通路，可減輕毛細(xì)胞死亡[106]。miR-183通過(guò)抑制的表達(dá),抑制誘導(dǎo)的細(xì)胞凋亡,調(diào)控TGF通路參與支持細(xì)胞和毛細(xì)胞的分化[107]。因此，通過(guò)下調(diào)和上調(diào)miRNA的表達(dá)來(lái)精準(zhǔn)調(diào)控耳蝸干細(xì)胞的發(fā)育進(jìn)程并減少毛細(xì)胞的凋亡是一種體內(nèi)原位毛細(xì)胞再生的可行策略[108]。miRNA調(diào)控耳蝸發(fā)育的分子機(jī)制示意圖見(jiàn)圖4。

5 miRNA在治療聾病方面應(yīng)用前景

目前已有6000余個(gè)miRNA被找到，這些miRNA與生物體中約1/3的蛋白編碼基因的調(diào)控密切相關(guān)[109]。miRNA已被證實(shí)是參與諸多內(nèi)耳相關(guān)的病理發(fā)生過(guò)程的關(guān)鍵因素，如漸進(jìn)性感音神經(jīng)性耳聾、老年化耳聾、噪聲性耳聾和內(nèi)耳炎癥等[110]。miRNA還參與了感覺(jué)毛細(xì)胞束發(fā)育、肌動(dòng)蛋白重組、細(xì)胞粘附和內(nèi)耳形態(tài)發(fā)生[111]。目前感音神經(jīng)性耳聾治療寄希望于毛細(xì)胞的移植治療，細(xì)胞移植的關(guān)鍵是獲得符合要求的毛細(xì)胞[90]。而獲得毛細(xì)胞的唯一途徑是來(lái)自于干細(xì)胞的體外誘導(dǎo)，所謂利用干細(xì)胞治療感音神經(jīng)性耳聾的最終目標(biāo)是將干細(xì)胞誘導(dǎo)分化，再移植到毛細(xì)胞受損傷的部位作為替代細(xì)胞，達(dá)到重建損傷耳蝸并修復(fù)聽(tīng)力功能[112]。近年來(lái)一系列的研究表明胚胎干細(xì)胞、間充質(zhì)干細(xì)胞、神經(jīng)干細(xì)胞、內(nèi)耳干細(xì)胞、iPS細(xì)胞等都可以在體外誘導(dǎo)分化為耳蝸類毛細(xì)胞[113]。然而，干細(xì)胞體外誘導(dǎo)獲得的耳蝸類毛細(xì)胞雖然可以表達(dá)毛細(xì)胞相關(guān)的標(biāo)志性蛋白，如Brn3c、Aoth1和MyosinⅦ等，但是掃描電鏡觀測(cè)到的類毛細(xì)胞的靜纖毛和動(dòng)纖毛仍與正常毛細(xì)胞的纖毛束有差距、神經(jīng)電生理也有差異[114]。miRNA已經(jīng)在毛囊細(xì)胞移植[115]、肝臟細(xì)胞體外分化[116]、心肌細(xì)胞體外分化[117]等方面有成功的案例。為此，本實(shí)驗(yàn)室構(gòu)建過(guò)表達(dá)miR-183、miR-182和miR-96的載體導(dǎo)入到胚胎干細(xì)胞，利用這種胚胎干細(xì)胞研究體外誘導(dǎo)分化為毛細(xì)胞的機(jī)理，希望獲得功能形態(tài)更加完整的毛細(xì)胞用于細(xì)胞移植治療[37]。

圖4 miRNA調(diào)控耳蝸發(fā)育的分子機(jī)制示意圖

∣表示正調(diào)控；⊥表示負(fù)調(diào)控。

6 結(jié)語(yǔ)與展望

耳聾是全球性的疾病問(wèn)題之一，世界上有5億人遭受聽(tīng)力喪失的困擾，其中包括了3200萬(wàn)名兒童[118]。根據(jù)中國(guó)殘聯(lián)的最新數(shù)據(jù)顯示：中國(guó)聽(tīng)力殘疾的人數(shù)已達(dá)2780萬(wàn)人，聽(tīng)力殘疾僅次于肢體殘疾，是中國(guó)第二大致殘疾病[119]。miRNA與耳蝸及毛細(xì)胞發(fā)育調(diào)控密切相關(guān)[120]，耳蝸中miRNA數(shù)量龐大，且一個(gè)miRNA可調(diào)控多個(gè)靶基因，多個(gè)miRNA也可協(xié)同調(diào)控一個(gè)靶基因，需要進(jìn)一步明確與耳聾相關(guān)聯(lián)的miRNA種類及生物特性。目前，miRNA在耳蝸中的具體分子機(jī)制尚未完全清楚，miRNA的成熟體究竟是在內(nèi)耳的單個(gè)細(xì)胞內(nèi)參與調(diào)控還是以外泌體等方式分泌到細(xì)胞外產(chǎn)生作用？?jī)?nèi)耳中表達(dá)了相同miRNA的細(xì)胞之間具有何種聯(lián)系？miRNA參與調(diào)控內(nèi)耳毛細(xì)胞纖毛束的具體作用方式是什么？這些問(wèn)題都值得人們深入探討。

另外，在耳蝸miRNA作用機(jī)理研究的基礎(chǔ)上，將來(lái)可用小分子化合物和關(guān)鍵的miRNA共同導(dǎo)入到耳蝸誘導(dǎo)毛細(xì)胞的原位再生，也可以用外泌體作為載體負(fù)載miRNA或者使用miRNA拮抗劑，移植耳蝸誘導(dǎo)毛細(xì)胞的原位再生。這些以miRNA為基礎(chǔ)的新技術(shù)，將為耳聾的治療提供新的思路。

[1] Dhungel B, Ramlogan-Steel CA, Steel JC. MicroRNA- regulated gene delivery systems for research and therapeutic purposes., 2018, 23(7): E1500.

[2] Lau NC, Lim LP, Weinstein EG, Bartel DP. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans., 2001, 294(5543): 858– 862.

[3] Tanzer A, Stadler PF. Molecular evolution of a micro-RNA cluster., 2004, 339(2): 327–335.

[4] Lagos-Quintana M, Rauhut R, Meyer J, Borkhardt A, Tuschl T. New microRNAs from mouse and human., 2003, 9(2): 175–179.

[5] Mittal R, Liu G, Polineni SP, Bencie N, Yan D, Liu XZ. Role of microRNAs in inner ear development and hearing loss., 2019, 686: 49–55.

[6] Mahmoodian Sani RM, Hashemzadeh-Chaleshtori M, Saidijam M, Jami MS, Ghasemi-Dehkordi P. Micro-RNA-183 family in inner ear: hair cell development and deafness., 2016, 20(3): 131–138.

[7] Fritzsch B, Elliott KL. Gene, cell, and organ multipli-cation drives inner ear evolution., 2017, 431(1): 3–15.

[8] Chan WX, Lee SH, Kim N, Shin CS, Yoon YJ. Mechanical model of an arched basilar membrane in the gerbil cochlea., 2017, 345: 1–9.

[9] Ulfendahl M, Khanna SM, Decraemer WF. Acoustically induced vibrations of the Reissner's membrane in the guinea-pig inner ear., 1996, 158(3): 275–285.

[10] Mahmoudian-sani MR, Mehri-Ghahfarrokhi A, Ahmadinejad F, Hashemzadeh-Chaleshtori M, Saidijam M, Jami MS. MicroRNAs: effective elements in ear-related diseases and hearing loss., 2017, 274(6): 2373–2380.

[11] Schrauwen I, Hasin-Brumshtein Y, Corneveaux JJ, Ohmen J, White C, Allen AN, Lusis AJ, Van Camp G, Huentelman MJ, Friedman RA. A comprehensive cata-logue of the coding and non-coding transcripts of the human inner ear., 2016, 333: 266–274.

[12] Mahmoodian-Sani MR, Mehri-Ghahfarrokhi A. The potential of miR-183 family expression in inner ear for regeneration, treatment, diagnosis and prognosis of hearing loss., 2017, 12(2): 55–61.

[13] Kwan KY. Single-cell transcriptome analysis of deve-loping and regenerating spiral ganglion neurons., 2016, 2(5): 211–220.

[14] Matsunami T, Suzuki T, Hisa Y, Takata K, Takamatsu T, Oyamada M. Gap junctions mediate glucose transport between GLUT1-positive and -negative cells in the spiral limbus of the rat cochlea., 2006, 13(1–2): 93–102.

[15] Lee SH, Ju HM, Choi JS, Ahn Y, Lee S, Seo YJ. Circulating serum miRNA-205 as a diagnostic biomar-ker for ototoxicity in mice treated with aminoglycoside antibiotics., 2018, 19(9): 2386.

[16] He WX, Kemp D, Ren TY. Timing of the reticular lamina and basilar membrane vibration in living gerbil cochleae., 2018, 7.

[17] Monzack EL, Cunningham LL. Lead roles for suppor-ting actors: critical functions of inner ear supporting cells., 2013, 303: 20–29.

[18] Liu J, Liu W, Yang J. ATP-containing vesicles in stria vascular marginal cell cytoplasms in neonatal rat cochlea are lysosomes., 2016, 6: 20903.

[19] Patel M, Hu BH. MicroRNAs in inner ear biology and pathogenesis., 2012, 287(1–2): 6–14.

[20] Torres L, Juárez U, García L, Miranda-Ríos J, Frias S. External ear microRNA expression profiles during mouse development., 2015, 59(10–12): 497–503.

[21] Trujillo-Provencio C, Powers TR, Sultemeier DR, Ramirez-Gordillo D, Serrano EE. RNA extraction from xenopus auditory and vestibular organs for molecular cloning and expression profiling with RNA-seq and microarrays., 2016, 1427: 73–92.

[22] Stenfelt S. Inner ear contribution to bone conduction hearing in the human., 2015, 329: 41–51.

[23] Whitfield TT. Development of the inner ear., 2015, 32: 112–118.

[24] Pechriggl EJ, Bitsche M, Glueckert R, Rask-Andersen H, Blumer MJF, Schrott-Fischer A, Fritsch H. Deve-lopment of the innervation of the human inner ear., 2015, 75(7): 683–702.

[25] Chadly DM, Best J, Ran C, Bruska M, Wo?niak W, Kempisty B, Schwartz M, LaFleur B, Kerns BJ, Kessler JA, Matsuoka AJ. Developmental profiling of micro-RNAs in the human embryonic inner ear., 2018, 13(1): e0191452.

[26] Sai XR, Ladher RK. Early steps in inner ear develop-ment: induction and morphogenesis of the otic placode., 2015, 6.

[27] McLean WJ, McLean DT, Eatock RA, Edge AS. Distinct capacity for differentiation to inner ear cell types by progenitor cells of the cochlea and vestibular organs., 2016, 143(23): 4381–4393.

[28] Corrales CE, Pan LY, Li HW, Liberman MC, Heller S, Edge AS. Engraftment and differentiation of embryonic stem cell-derived neural progenitor cells in the cochlear nerve trunk: Growth of processes into the organ of corti., 2006, 66(13): 1489–1500.

[29] Varela-Nieto I, Palmero I, Magari?os M. Complemen-tary and distinct roles of autophagy, apoptosis and sene-scence during early inner ear development., 2019, 376: 86–96.

[30] Robles L, Ruggero MA. Mechanics of the mammalian cochlea., 2001, 81(3): 1305–1352.

[31] Hurd EA, Adams ME, Layman WS, Swiderski DL, Beyer LA, Halsey KE, Benson JM, Gong TW, Dolan DF, Raphael Y, Martin DM. Mature middle and inner ears express Chd7 and exhibit distinctive pathologies in a mouse model of CHARGE syndrome., 2011, 282(1–2): 184–195.

[32] Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T. Identification of tissue-specific microRNAs from mouse., 2002, 12(9): 735– 739.

[33] Berghaus A, Nicoló MS. Milestones in the history of ear reconstruction., 2015, 31(6): 563– 566.

[34] Lee S, Shin JO, Sagong B, Kim UK, Bok J. Spatiotem-poral expression patterns of clusterin in the mouse inner ear., 2017, 370(1): 89–97.

[35] Roser AE, Gomes LC, Halder R, Jain G, Maass F, T?nges L, Tatenhorst L, B?hr M, Fischer A, Lingor P. miR-182-5p and miR-183-5p Act as GDNF mimics in dopaminergic midbrain neurons., 2018, 11: 9–22.

[36] Bai YS, Li L, Wei HX, Zhu C, Zhang CQ. The effect of microRNAs on the regulatory network of pluripotency in embryonic stem cells., 2013, 35(10): 1153–1166.白銀山, 李莉, 衛(wèi)恒習(xí), 朱翠, 張守全. MicroRNA對(duì)胚胎干細(xì)胞的多能性網(wǎng)絡(luò)調(diào)控. 遺傳, 2013, 35(10): 1153–1166.

[37] Weston MD, Tarang S, Pierce ML, Pyakurel U, Rocha-Sanchez SM, McGee J, Walsh EJ, Soukup GA. A mouse model of miR-96, miR-182 and miR-183 misex-pression implicates miRNAs in cochlear cell fate and homeostasis., 2018, 8(1): 3569.

[38] Weston MD, Pierce ML, Rocha-Sanchez S, Beisel KW, Soukup GA. MicroRNA gene expression in the mouse inner ear., 2006, 1111(1): 95–104.

[39] Li HQ, Kloosterman W, Fekete DM. MicroRNA-183 family members regulate sensorineural fates in the inner ear., 2010, 30(9): 3254–3263.

[40] Xiang L, Chen XJ, Wu KC, Zhang CJ, Zhou GH, Lv JN, Sun LF, Cheng FF, Cai XB, Jin ZB. miR-183/96 plays a pivotal regulatory role in mouse photoreceptor matura-tion and maintenance., 2017, 114(24): 6376–6381.

[41] Sacheli R, Nguyen L, Borgs L, Vandenbosch R, Bodson M, Lefebvre P, Malgrange B. Expression patterns of miR-96, miR-182 and miR-183 in the development inner ear., 2009, 9(5): 364–370.

[42] Fettiplace R. Hair cell transduction, tuning, and synaptic transmission in the mammalian cochlea., 2017, 7(4): 1197–1227.

[43] Cunningham LL, Tucci DL. Hearing loss in adults., 2017, 377(25): 2465–2473.

[44] Liberman MC, Epstein MJ, Cleveland SS, Wang HB, Maison SF. Toward a differential diagnosis of hidden hearing loss in humans., 2016, 11(9): e0162726.

[45] Berrettini S, De Vito A, Bruschini L, Fortunato S, Forli F. Idiopathic sensorineural hearing loss in the only hearing ear., 2016, 36(2): 119–126.

[46] Leung MA, Flaherty A, Zhang JA, Hara J, Barber W, Burgess L. Sudden sensorineural hearing loss: primary care update., 2016, 75(6): 172–174.

[47] Bermingham-McDonogh O, Reh TA. Regulated repro-gramming in the regeneration of sensory receptor cells., 2011, 71(3): 389–405.

[48] Sekine K, Matsumura T, Takizawa T, Kimura Y, Saito S, Shiiba K, Shindo S, Okubo K, Ikezono T. Expression profiling of MicroRNAs in the inner ear of elderly people by real-time PCR quantification., 2017, 22(3): 135–145.

[49] Pierce ML, Weston MD, Fritzsch B, Gabel HW, Ruvkun G, Soukup GA. MicroRNA-183 family conservation and ciliated neurosensory organ expression., 2008, 10(1): 106–113.

[50] Dambal S, Baumann B, McCray T, Williams L, Richards Z, Deaton R, Prins GS, Nonn L. The miR-183 family cluster alters zinc homeostasis in benign prostate cells, organoids and prostate cancer xenografts., 2017, 7(1): 7704.

[51] Xu S, Witmer PD, Lumayag S, Kovacs B, Valle D. MicroRNA (miRNA) transcriptome of mouse retina and identification of a sensory organ-specific miRNA cluster., 2007, 282(34): 25053–25066.

[52] Li JY, Ling YH, Huang WH, Sun LM, Li YY, Wang CH, Zhang YH, Wang XD, Dahlgren RA, Wang HL. Regu-latory mechanisms of miR-96 and miR-184 abnormal expressions on otic vesicle development of zebrafish following exposure to β-diketone antibiotics., 2019, 214: 228–238.

[53] Raymond M, Walker E, Dave I, Dedhia K. Genetic testing for congenital non-syndromic sensorineural hearing loss., 2019, 124: 68–75.

[54] Li HQ, Fekete DM. MicroRNAs in hair cell develop-ment and deafness., 2010, 18(5): 459–465.

[55] Chen J, Johnson SL, Lewis MA, Hilton JM, Huma A, Marcotti W, Steel KP. A reduction in Ptprq associated with specific features of the deafness phenotype of the miR-96 mutant mouse diminuendo., 2014, 39(5): 744–756.

[56] Sánchez-Mora C, Ramos-Quiroga JA, Garcia-Martínez I, Fernàndez-Castillo N, Bosch R, Richarte V, Palomar G, Nogueira M, Corrales M, Daigre C, Martínez-Luna N, Grau-Lopez L, Toma C, Cormand B, Roncero C, Casas M, Ribasés M. Evaluation of single nucleotide polymo-rphisms in the miR-183-96-182 cluster in adulthood attention-deficit and hyperactivity disorder (ADHD) and substance use disorders (SUDs)., 2013, 23(11): 1463–1473.

[57] Mencía A, Modamio-H?ybj?r S, Redshaw N, Morín M, Mayo-Merino F, Olavarrieta L, Aguirre LA, del Castillo I, Steel KP, Dalmay T, Moreno F, Moreno-Pelayo MA. Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss., 2009, 41(5): 609–613.

[58] Lewis MA, Quint E, Glazier AM, Fuchs H, De Angelis MH, Langford C, van Dongen S, Abreu-Goodger C, Piipari M, Redshaw N, Dalmay T, Moreno-Pelayo MA, Enright AJ, Steel KP. An ENU-induced mutation of miR-96 associated with progressive hearing loss in mice., 2009, 41(5): 614–618.

[59] Kuhn S, Johnson SL, Furness DN, Chen J, Ingham N, Hilton JM, Steffes G, Lewis MA, Zampini V, Hackney CM, Masetto S, Holley MC, Steel KP, Marcotti W. miR-96 regulates the progression of differentiation in mammalian cochlear inner and outer hair cells., 2011, 108(6): 2355–2360.

[60] Li YM, Li A, Wu JF, He YZ, Yu HQ, Chai RJ. MiR- 182-5p protects inner ear hair cells from cisplatin- induced apoptosis by inhibiting FOXO3a., 2016, 7(9): e2362.

[61] Patel M, Cai QF, Ding DL, Salvi R, Hu ZH, Hu BH. The miR-183/Taok1 target pair is implicated in cochlear responses to acoustic trauma., 2013, 8(3): e58471.

[62] MacFarlane LA, Murphy PR. MicroRNA: biogenesis, function and role in cancer., 2010, 11(7): 537–561.

[63] Giraldez AJ, Cinalli RM, Glasner ME, Enright AJ, Thomson JM, Baskerville S, Hammond SM, Bartel DP, Schier AF. MicroRNAs regulate brain morphogenesis in zebrafish., 2005, 308(5723): 833–838.

[64] Weston MD, Pierce ML, Jensen-Smith HC, Fritzsch B, Rocha-Sanchez S, Beisel KW, Soukup GA. MicroRNA- 183 family expression in hair cell development and requirement of MicroRNAs for hair cell maintenance and survival., 2011, 240(4): 808–819.

[65] Hildebrand MS, Witmer PD, Xu S, Newton SS, Kahrizi K, Najmabadi H, Valle D, Smith RJ. miRNA mutations are not a common cause of deafness., 2010, 152A(3): 646–652.

[66] Wang XR, Zhang XM, Du JT, Jiang HY. MicroRNA-182 regulates otocyst-derived cell differentiation and targets T-box1 gene., 2012, 286(1–2): 55–63.

[67] Schellenberg GD, Dawson G, Sung YJ, Estes A, Munson J, Rosenthal E, Rothstein J, Flodman P, Smith M, Coon H, Leong L, Yu CE, Stodgell C, Rodier PM, Spence MA, Minshew N, McMahon WM, Wijsman EM. Evidence for multiple loci from a genome scan of autism kindreds., 2006, 11(11): 1049– 1060.

[68] Soukup GA, Fritzsch B, Pierce ML, Weston MD, Jahan I, McManus MT, Harfe BD. Residual microRNA expression dictates the extent of inner ear development in conditional dicer knockout mice., 2009, 328(2): 328–341.

[69] Bhattacharya A, Cui Y. Knowledge-based analysis of functional impacts of mutations in microRNA seed regions., 2015, 40(4): 791–798.

[70] Kim CW, Han JH, Wu L, Choi JY. microRNA-183 is essential for hair cell regeneration after neomycin injury in zebrafish., 2018, 59(1): 141–147.

[71] Van den Ackerveken P, Mounier A, Huyghe A, Sacheli R, Vanlerberghe PB, Volvert ML, Delacroix L, Nguyen L, Malgrange B. The miR-183/ItgA3 axis is a key regulator of prosensory area during early inner ear development., 2017, 24(12): 2054– 2065.

[72] Sivakumaran TA, Resendes BL, Robertson NG, Giersch ABS, Morton CC. Characterization of an abundant COL9A1 transcript in the cochlea with a novel 3? UTR: Expression studies and detection of miRNA target sequence., 2006, 7(2): 160–172.

[73] Gu CH, Li XD, Tan Q, Wang Z, Chen LM, Liu YM. MiR-183 family regulates chloride intracellular channel 5 expression in inner ear hair cells., 2013, 27(1): 486–491.

[74] Jiang D, Du JT, Zhang XM, Zhou W, Zong L, Dong C, Chen K, Chen Y, ChenXH, Jiang HY. miR-124 promotes the neuronal differentiation of mouse inner ear neural stem cells., 2016, 38(5): 1367–1376.

[75] Rudnicki A, Isakov O, Ushakov K, Shivatzki S, Weiss I, Friedman LM, Shomron N, Avraham KB. Next-gene-ration sequencing of small RNAs from inner ear sensory epithelium identifies microRNAs and defines regulatory pathways., 2014, 15: 484.

[76] Du JT, Zhang XM, Cao H, Jiang D, Wang XR, Zhou W, Chen KT, Zhou J, Jiang HY, Ba L. MiR-194 is involved in morphogenesis of spiral ganglion neurons in inner ear by rearranging actin cytoskeleton via targeting RhoB., 2017, 63: 16–26.

[77] Park SM, Gaur AB, Lengyel E, Peter ME. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2., 2008, 22(7): 894–907.

[78] Yan D, Xing YZ, Ouyang XM, Zhu JH, Chen ZY, Lang HN, Liu XZ. Analysis of miR-376 RNA cluster members in the mouse inner ear., 2012, 93(6): 450–457.

[79] Elkan-Miller T, Ulitsky I, Hertzano R, Rudnicki A, Dror AA, Lenz DR, Elkon R, Irmler M, Beckers J, Shamir R, Avraham KB. Integration of transcriptomics, proteomics, and microRNA analyses reveals novel microRNA regulation of targets in the mammalian inner ear., 2011, 6(4): e18195.

[80] Kurtz CL, Fannin EE, Toth CL, Pearson DS, Vickers KC, Sethupathy P. Inhibition of miR-29 has a signi-ficant lipid-lowering benefit through suppression of lipogenic programs in liver., 2015, 5: 12911.

[81] Pang JQ, Xiong H, Yang HD, Ou YK, Xu YD, Huang QH, Lai L, Chen SJ, Zhang ZG, Cai YX, Zheng YQ. Circulating miR-34a levels correlate with age-related hearing loss in mice and humans., 2016, 76: 58–67.

[82] Ling H, Fabbri M, Calin GA. MicroRNAs and other non-coding RNAs as targets for anticancer drug develo-pment., 2013, 12(11): 847–865.

[83] Chiang DY, Cuthbertson DW, Ruiz FR, Li N, Pereira FA. A coregulatory network of NR2F1 and microRNA-140., 2013, 8(12): e83358.

[84] Lee YJ, Bernstock JD, Klimanis D, Hallenbeck JM. Akt protein kinase, miR-200/miR-182 expression and epithelial- mesenchymal transition proteins in hibernating ground squirrels., 2018, 11: 22.

[85] Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S, Brabletz T. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells., 2008, 9(6): 582–589.

[86] Li YZ, Peng AQ, Ge SL, Wang Q, Liu JJ. miR-204 suppresses cochlear spiral ganglion neuron survival in vitro by targeting TMPRSS3., 2014, 314: 60–64.

[87] Rudnicki A, Shivatzki S, Beyer LA, Takada Y, Raphael Y, Avraham KB. microRNA-224 regulates Pentraxin 3, a component of the humoral arm of innate immunity, in inner ear inflammation., 2014, 23(12): 3138–3146.

[88] Kiernan AE, Xu JX, Gridley T. The Notch ligand JAG1 is required for sensory progenitor development in the mammalian inner ear., 2006, 2(1): e4.

[89] Pan BF, Akyuz N, Liu XP, Asai Y, Nist-Lund C, Kurima K, Derfler BH, Gyorgy B, Limapichat W, Walujkar S, Wimalasena LN, Sotomayor M, Corey DP, Holt JR. TMC1 forms the pore of mechanosensory transduction channels in vertebrate inner ear hair cells., 2018, 99(4): 736–753.e6.

[90] Müller U, Barr-Gillespie PG. New treatment options for hearing loss., 2015, 14(5): 346– 385.

[91] Bermingham NA, Hassan BA, Price SD, Vollrath MA, Ben-Arie N, Eatock RA, Bellen HJ, Lysakowski A, Zoghbi HY. Math1: an essential gene for the generation of inner ear hair cells., 1999, 284(5421): 1837– 1841.

[92] Fan QQ, Meng FL, Fang R, Li GP, Zhao XL. Functions of Wnt signaling pathway in hair cell differentiation and regeneration., 2017, 39(10): 897–907.范晴晴, 孟飛龍, 房冉, 李高鵬, 趙小立. Wnt信號(hào)通路在毛細(xì)胞分化和再生過(guò)程中的作用. 遺傳, 2017, 39(10): 897–907.

[93] Slowik AD, Bermingham-McDonogh O. Hair cell generation by notch inhibition in the adult mammalian cristae., 2013, 14(6): 813–828.

[94] Tateya T, Imayoshi I, Tateya I, Hamaguchi K, Torii H, Ito J, Kageyama R. Hedgehog signaling regulates prosensory cell properties during the basal-to-apical wave of hair cell differentiation in the mammalian cochlea., 2013, 140(18): 3848–3857.

[95] Mansour SL, Noyes CA, Li CY, Wang XF, Hatch E, Twigg S, WIlkie AOM, Urness L. FGF signaling in inner ear development., 2009, 23.

[96] Kim HJ, Kang KY, Baek JG, Jo HC, Kim H. Expression of TGFβ family in the developing internal ear of rat embryos., 2006, 21(1): 136–142.

[97] Geng RS, Noda T, Mulvaney JF, Lin VYW, Edge ASB, Dabdoub A. Comprehensive expression of wnt signaling pathway genes during development and maturation of the mouse cochlea., 2016, 11(2): e0148339.

[98] Chen C, Xiang H, Peng YL, Peng J, Jiang SW. Mature miR-183, negatively regulated by transcription factor GATA3, promotes 3T3-L1 adipogenesis through inhibition of the canonical Wnt/β-catenin signaling pathway by targeting LRP6., 2014, 26(6): 1155–1165.

[99] Tang XL, Zheng D, Hu P, Zeng ZY, Li M, Tucker L, Monahan R, Resnick MB, Liu M, Ramratnam B. Glycogen synthase kinase 3 beta inhibits microRNA- 183-96-182 cluster via the β-Catenin/TCF/LEF-1 pathway in gastric cancer cells., 2014, 42(5): 2988–2998.

[100] Hartman BH, Reh TA, Bermingham-McDonogh O. Notch signaling specifies prosensory domains via lateral induction in the developing mammalian inner ear., 2010, 107(36): 15792–15797.

[101] Chen ZB Pu MM, Yao J, Cao X, Cheng L. Screening of microRNAs targeting Notch signaling pathway implicated in inner ear development and the role of microRNA-384-5p., 2018, 53(11): 830–837.

[102] Zhou W, Du JT, Jiang D, Wang XR, Chen KT, Tang HC, Zhang XM, Cao H, Zong L, Dong C, Jiang HY. microRNA-183 is involved in the differentiation and regeneration of Notch signaling-prohibited hair cells from mouse cochlea., 2018, 18(2): 1253– 1262.

[103] Yang Z, Yao J, Cao X. Roles of the FGF signaling pathway in regulating inner ear development and hair cell regeneration., 2018, 40(7): 515– 524 楊志, 姚俊, 曹新. FGF信號(hào)通路在內(nèi)耳發(fā)育調(diào)控和毛細(xì)胞再生中的作用. 遺傳, 2018, 40(7): 515–524.

[104] Brennecke J, Hipfner DR, Stark A, Russell RB, Cohen SM. Bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in., 2003, 113(1): 25–36.

[105] Tan PX, Du SS, Ren C, Yao QW, Zheng R, Li R, Yuan YW. MicroRNA-207 enhances radiation-induced apoptosis by directly targeting akt3 in cochlea hair cells., 2014, 5: e1433.

[106] Yamashita H, Takahashi M, Bagger-Sj?b?ck D. Expression of epidermal growth factor, epidermal growth factor receptor and transforming growth factor-alpha in the human fetal inner ear., 1996, 253(8): 494–497.

[107] Lu YY, Zheng JY, Liu J, Huang CL, Zhang W, Zeng Y. miR-183 induces cell proliferation, migration, and invasion by regulating PDCD4 expression in the SW1990 panc-reatic cancer cell line., 2015, 70: 151–157.

[108] Mendell JT, Olson EN. MicroRNAs in stress signaling and human disease., 2012, 148(6): 1172–1187.

[109] Cui J, Zhou B, Ross SA, Zempleni J. Nutrition, microRNAs, and human health., 2017, 8(1): 105–112.

[110] Miguel V, Cui JY, Daimiel L, Espinosa-Díez C, Fernández-Hernando C, Kavanagh TJ, Lamas S. The role of microRNAs in environmental risk factors, noise- induced hearing loss, and mental stress., 2018, 28(9): 773–796.

[111] Bardin P, Sonneville F, Corvol H, Tabary O. Emerging microRNA therapeutic approaches for cystic fibrosis., 2018, 9: 1113.

[112] Takeda H, Dondzillo A, Randall JA, Gubbels SP. Challenges in cell-based therapies for the treatment of hearing loss., 2018, 41(11): 823–837.

[113] Simoni E, Orsini G, Chicca M, Bettini S, Franceschini V, Martini A, Astolfi L. Regenerative medicine in hearing recovery., 2017, 19(8): 909–915.

[114] Shrestha BR, Chia C, Wu L, Kujawa SG, Liberman MC, Goodrich LV. Sensory neuron diversity in the inner ear is shaped by activity., 2018, 174(5): 1229–1246.e17.

[115] Sennett R, Rendl M. Mesenchymal-epithelial interactions during hair follicle morphogenesis and cycling., 2012, 23(8): 917–927.

[116] Chen H, Sun YM, Dong RQ, Yang SS, Pan CY, Xiang D, Miao MY, Jiao BH. Mir-34a is upregulated during liver regeneration in rats and is associated with the supper-ssion of hepatocyte proliferation., 2011, 6(5): e20238.

[117] Liang DD, Li J, Wu YH, Zhen LX, Li CM, Qi M, Wang LJ, Deng FF, Huang J, Lv F, Liu Y, Ma C, Yu ZR, Zhang YZ, Chen YH. miRNA-204 drives cardiomyocyte proliferation via targeting Jarid2., 2015, 201: 38–48.

[118] Vos T, Abajobir AA, Abate KH, Abbafati C, Abbas KM, Abd-Allah F, Abdulkader RS, Abdulle AM, Abebo TA, Abera SF, Aboyans V, Abu-Raddad LJ, Ackerman IN, Adamu AA, Adetokunboh O, Afarideh M, Afshin A, Agarwal SK, Aggarwal R, Agrawal A, Agrawal S, Ahmadieh H, Ahmed MB, Aichour MTE, Aichour AN, Aichour I, Aiyar S, Akinyemi RO, Akseer N, Al Lami FH, Alahdab F, Al-Aly Z, Alam K, Alam N, Alam T, Alasfoor D, Alene KA, Ali R, Alizadeh-Navaei R, Alkerwi A, Alla F, Allebeck P, Allen C, Al-Maskari F, Al-Raddadi R, Alsharif U, Alsowaidi S, Altirkawi KA, Amare AT, Amini E, Ammar W, Amoako YA, Andersen HH, Antonio CAT, Anwari P, ?rnl?v J, Artaman A, Aryal KK, Asayesh H, Asgedom SW, Assadi R, Atey TM, Atnafu NT, Atre SR, Avila-Burgos L, Avokphako EFGA, Awasthi A, Bacha U, Badawi A, Balakrishnan K, Banerjee A, Bannick MS, Barac A, Barber RM, Barker- Collo SL, B?rnighausen T, Barquera S, Barregard L, Barrero LH, Basu S, Battista B, Battle KE, Baune BT, Bazargan-Hejazi S, Beardsley J, Bedi N, Beghi E, Béjot Y, Bekele BB, Bell ML, Bennett DA, Bensenor IM, Benson J, Berhane A, Berhe DF, Bernabé E, Betsu BD, Beuran M, Beyene AS, Bhala N, Bhansali A, Bhatt S, Bhutta ZA, Biadgilign S, Bicer BK, Bienhoff K, Bikbov B, Birungi C, Biryukov S, Bisanzio D, Bizuayehu HM, Boneya DJ, Boufous S, Bourne RRA, Brazinova A, Brugha TS, Buchbinder R, Bulto LNB, Bumgarner BR, Butt ZA, Cahuana-Hurtado L, Cameron E, Car M, Carabin H, Carapetis JR, Cárdenas R, Carpenter DO, Carrero JJ, Carter A, Carvalho F, Casey DC, Caso V, Casta?eda-Orjuela CA, Castle CD, Catalá-López F, Chang HY, Chang JC, Charlson FJ, Chen H, Chibalabala M, Chibueze CE, Chisumpa VH, Chitheer AA, Christopher DJ, Ciobanu LG, Cirillo M, Colombara D, Cooper C, Cortesi PA, Criqui MH, Crump JA, Dadi AF, Dalal K, Dandona L, Dandona R, das Neves J, Davitoiu DV, de Courten B, De Leo D, Defo BK, Degenhardt L, Deiparine S, Dellavalle RP, Deribe K, Des Jarlais DC, Dey S, Dharmaratne SD, Dhillon PK, Dicker D, Ding EL, Djalalinia S, Do HP, Dorsey ER, Dos Santos KPB, Douwes-Schultz D, Doyle KE, Driscoll TR, Dubey M, Duncan BB, El-Khatib ZZ, Ellerstrand J, Enayati A, Endries AY, Ermakov SP, Erskine HE, Eshrati B, Eskandarieh S, Esteghamati A, Estep K, Fanuel FBB, Farinha CSES, Faro A, Farzadfar F, Fazeli MS, Feigin VL, Fereshtehnejad SM, Fernandes JC, Ferrari AJ, Feyissa TR, Filip I, Fischer F, Fitzmaurice C, Flaxman AD, Flor LS, Foigt N, Foreman KJ, Franklin RC, Fullman N, Fürst T, Furtado JM, Futran ND, Gakidou E, Ganji M, Garcia-Basteiro AL, Gebre T, Gebrehiwot TT, Geleto A, Gemechu BL, Gesesew HA, Gething PW, Ghajar A, Gibney KB, Gill PS, Gillum RF, Ginawi IAM, Giref AZ, Gishu MD, Giussani G, Godwin WW, Gold AL, Goldberg EM, Gona PN, Goodridge A, Gopalani SV, Goto A, Goulart AC, Griswold M, Gugnani HC, Gupta R, Gupta R, Gupta T, Gupta V, Hafezi-Nejad N, Hailu GB, Hailu AD, Hamadeh RR, Hamidi S, Handal AJ, Hankey GJ, Hanson SW, Hao Y, Harb HL, Hareri HA, Haro JM, Harvey J, Hassanvand MS, Havmoeller R, Hawley C, Hay SI, Hay RJ, Henry NJ, Heredia-Pi IB, Hernandez JM, Heydarpour P, Hoek HW, Hoffman HJ, Horita N, Hosgood HD, Hostiuc S, Hotez PJ, Hoy DG, Htet AS, Hu G, Huang H, Huynh C, Iburg KM, Igumbor EU, Ikeda C, Irvine CMS, Jacobsen KH, Jahanmehr N, Jakovljevic MB, Jassal SK, Javanbakht M, Jayaraman SP, Jeemon P, Jensen PN, Jha V, Jiang G, John D, Johnson SC, Johnson CO, Jonas JB, Jürisson M, Kabir Z, Kadel R, Kahsay A, Kamal R, Kan H, Karam NE, Karch A, Karema CK, Kasaeian A, Kassa GM, Kassaw NA, Kassebaum NJ, Kastor A, Katikireddi SV, Kaul A, Kawakami N, Keiyoro PN, Kengne AP, Keren A, Khader YS, Khalil IA, Khan EA, Khang YH, Khosravi A, Khubchandani J, Kiadaliri AA, Kieling C, Kim YJ, Kim D, Kim P, Kimokoti RW, Kinfu Y, Kisa A, Kissimova-Skarbek KA, Kivimaki M, Knudsen AK, Kokubo Y, Kolte D, Kopec JA, Kosen S, Koul PA, Koyanagi A, Kravchenko M, Krishnaswami S, Krohn KJ, Kumar GA, Kumar P, Kumar S, Kyu HH, Lal DK, Lalloo R, Lambert N, Lan Q, Larsson A, Lavados PM, Leasher JL, Lee PH, Lee JT, Leigh J, Leshargie CT, Leung J, Leung R, Levi M, Li Y, Li Y, Li Kappe D, Liang X, Liben ML, Lim SS, Linn S, Liu PY, Liu A, Liu S, Liu Y, Lodha R, Logroscino G, London SJ, Looker KJ, Lopez AD, Lorkowski S, Lotufo PA, Low N, Lozano R, Lucas TCD, Macarayan ERK, Magdy Abd El Razek H, Magdy Abd El Razek M, Mahdavi M, Majdan M, Majdzadeh R, Majeed A, Malekzadeh R, Malhotra R, Malta DC, Mamun AA, Manguerra H, Manhertz T, Mantilla A, Mantovani LG, Mapoma CC, Marczak LB, Martinez-Raga J, Martins-Melo FR, Martopullo I, M?rz W, Mathur MR, Mazidi M, McAlinden C, McGaughey M, McGrath JJ, McKee M, McNellan C, Mehata S, Mehndiratta MM, Mekonnen TC, Memiah P, Memish ZA, Mendoza W, Mengistie MA, Mengistu DT, Mensah GA, Meretoja TJ, Meretoja A, Mezgebe HB, Micha R, Millear A, Miller TR, Mills EJ, Mirarefin M, Mirrakhimov EM, Misganaw A, Mishra SR, Mitchell PB, Mohammad KA, Mohammadi A, Mohammed KE, Mohammed S, Mohanty SK, Mokdad AH, Mollenkopf SK, Monasta L, Montico M, Moradi-Lakeh M, Moraga P, Mori R, Morozoff C, Morrison SD, Moses M, Mountjoy-Venning C, Mruts KB, Mueller UO, Muller K, Murdoch ME, Murthy GVS, Musa KI, Nachega JB, Nagel G, Naghavi M, Naheed A, Naidoo KS, Naldi L, Nangia V, Natarajan G, Negasa DE, Negoi RI, Negoi I, Newton CR, Ngunjiri JW, Nguyen TH, Nguyen QL, Nguyen CT, Nguyen G, Nguyen M, Nichols E, Ningrum DNA, Nolte S, Nong VM, Norrving B, Noubiap JJN, O'Donnell MJ, Ogbo FA, Oh IH, Okoro A, Oladimeji O, Olagunju TO, Olagunju AT, Olsen HE, Olusanya BO, Olusanya JO, Ong K, Opio JN, Oren E, Ortiz A, Osgood-Zimmerman A, Osman M, Owolabi MO, Pa M, Pacella RE, Pana A, Panda BK, Papachristou C, Park EK, Parry CD, Parsaeian M, Patten SB, Patton GC, Paulson K, Pearce N, Pereira DM, Perico N, Pesudovs K, Peterson CB, Petzold M, Phillips MR, Pigott DM, Pillay JD, Pinho C, Plass D, Pletcher MA, Popova S, Poulton RG, Pourmalek F, Prabhakaran D, Prasad NM, Prasad N, Purcell C, Qorbani M, Quansah R, Quintanilla BPA, Rabiee RHS, Radfar A, Rafay A, Rahimi K, Rahimi-Movaghar A, Rahimi-Movaghar V, Rahman MHU, Rahman M, Rai RK, Rajsic S, Ram U, Ranabhat CL, Rankin Z, Rao PC, Rao PV, Rawaf S, Ray SE, Reiner RC, Reinig N, Reitsma MB, Remuzzi G, Renzaho AMN, Resnikoff S, Rezaei S, Ribeiro AL, Ronfani L, Roshandel G, Roth GA, Roy A, Rubagotti E, Ruhago GM, Saadat S, Sadat N, Safdarian M, Safi S, Safiri S, Sagar R, Sahathevan R, Salama J, Saleem HOB, Salomon JA, Salvi SS, Samy AM, Sanabria JR, Santomauro D, Santos IS, Santos JV, Santric Milicevic MM, Sartorius B, Satpathy M, Sawhney M, Saxena S, Schmidt MI, Schneider IJC, Sch?ttker B, Schwebel DC, Schwendicke F, Seedat S, Sepanlou SG, Servan-Mori EE, Setegn T, Shackelford KA, Shaheen A, Shaikh MA, Shamsipour M, Shariful Islam SM, Sharma J, Sharma R, She J, Shi P, Shields C, Shifa GT, Shigematsu M, Shinohara Y, Shiri R, Shirkoohi R, Shirude S, Shishani K, Shrime MG, Sibai AM, Sigfusdottir ID, Silva DAS, Silva JP, Silveira DGA, Singh JA, Singh NP, Sinha DN, Skiadaresi E, Skirbekk V, Slepak EL, Sligar A, Smith DL, Smith M, Sobaih BHA, Sobngwi E, Sorensen RJD, Sousa TCM, Sposato LA, Sreeramareddy CT, Srinivasan V, Stanaway JD, Stathopoulou V, Steel N, Stein MB, Stein DJ, Steiner TJ, Steiner C, Steinke S, Stokes MA, Stovner LJ, Strub B, Subart M, Sufiyan MB, Sunguya BF, Sur PJ, Swaminathan S, Sykes BL, Sylte DO, Tabarés-Seisdedos R, Taffere GR, Takala JS, Tandon N, Tavakkoli M, Taveira N, Taylor HR, Tehrani-Banihashemi A, Tekelab T, Terkawi AS, Tesfaye DJ, Tesssema B, Thamsuwan O, Thomas KE, Thrift AG, Tiruye TY, Tobe-Gai R, Tollanes MC, Tonelli M, Topor-Madry R, Tortajada M, Touvier M, Tran BX, Tripathi S, Troeger C, Truelsen T, Tsoi D, Tuem KB, Tuzcu EM, Tyrovolas S, Ukwaja KN, Undurraga EA, Uneke CJ, Updike R, Uthman OA, Uzochukwu BSC, van Boven JFM, Varughese S, Vasankari T, Venkatesh S, Venketasubramanian N, Vidavalur R, Violante FS, Vladimirov SK, Vlassov VV, Vollset SE, Wadilo F, Wakayo T, Wang YP, Weaver M, Weichenthal S, Weiderpass E, Weintraub RG, Werdecker A, Westerman R, Whiteford HA, Wijeratne T, Wiysonge CS, Wolfe CDA, Woodbrook R, Woolf AD, Workicho A, Xavier D, Xu G, Yadgir S, Yaghoubi M, Yakob B, Yan LL, Yano Y, Ye P, Yimam HH, Yip P, Yonemoto N, Yoon SJ, Yotebieng M, Younis MZ, Zaidi Z, Zaki MES, Zegeye EA, Zenebe ZM, Zhang X, Zhou M, Zipkin B, Zodpey S, Zuhlke LJ, Murray CJL. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016., 2017, 390(10100): 1211–1259.

[119] He P, Luo YN, Hu XY, Gong R, Wen X, Zheng XY. Association of socioeconomic status with hearing loss in Chinese working-aged adults: A population-based study., 2018, 13(3): e0195227.

[120] Soukup GA. Little but loud: Small RNAs have a resounding affect on ear development., 2009, 1277: 104–114.

Molecular mechanism of microRNA in regulating cochlear hair cell development

Lin Rao, Feilong Meng, Ran Fang, Chenyi Cai, Xiaoli Zhao

Deafness has become one of the most frequent health problems worldwide, and affects almost every age group. Hair cell damage or absence is the main cause of hearing loss, but there is no successful treatment to heal deafness. MicroRNA (miRNA), as a highly conserved endogenous non-coding small RNA, plays an important role in inner ear cochlea and hair cell development. In this review, we elaborate on the expression and function of miRNAs in cochlear hair cell development, and reveal its indispensable important role. We summarize the molecular mechanism of miRNA in regulating transcription factors involved in cochlear hair cell development, which may provide references and insights for hair cell regenerationand cellular transplantation therapy of deafness.

miRNA; cochlea; hearing loss; hair cells

2019-07-20;

2019-09-26

國(guó)家重點(diǎn)基礎(chǔ)研究發(fā)展規(guī)劃項(xiàng)目(973計(jì)劃) (編號(hào)：2012CB967900)資助[Supported by the National Program on Key Basic Research Project (973 Program) (No. 2012CB967900)]

饒琳，碩士研究生，專業(yè)方向：干細(xì)胞分化。E-mail: 21707038@zju.edu.cn

趙小立，副教授，碩士生導(dǎo)師，研究方向：干細(xì)胞分化。E-mail: zhaoxiaoli@zju.edu.cn

10.16288/j.yczz.19-119

2019/10/29 16:01:28

URI: http://kns.cnki.net/kcms/detail/11.1913.R.20191029.1042.003.html

(責(zé)任編委: 袁慧軍)