慢病毒介导的FoxP2 knockdown蝙蝠模型建立与功能研究及长翼蝠小RNA转录组的分析研究
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摘要
1.Forkhead box P2(FoxP2)是转录因子叉头框基因家族的一员,FOXP2基因的突变导致了人类语言疾病。在具有复杂发声能力的鸣禽中FoxP2基因被认为与幼鸟鸣曲学习和成鸟鸣曲稳定性有关。最近有研究表明该基因在翼手目蝙蝠中发生了加速进化并认为FoxP2基因与蝙蝠的回声定位功能相关。为进一步探索FoxP2基因与蝙蝠复杂的高频发声功能之间的相关性,我们利用免疫组化和原位杂交技术在蛋白质水平和mRNA水平对3种回声定位蝙蝠(马铁菊头蝠,大足鼠耳蝠和大蹄蝠)和2种非回声定位蝙蝠(棕果蝠和犬蝠)脑中的FoxP2基因差异表达谱进行了研究。两类蝙蝠中前扣带皮层有不同的FoxP2表达。本文首次利用慢病毒介导的RNAi手段对大蹄蝠脑FoxP2基因进行了功能丧失实验。我们设计了三条可以靶向大蹄蝠FoxP2基因的shRNA干扰序列,其中一条可以在293T细胞系成功抑制FoxP2融合蛋白的表达。为深入研究FoxP2在动物体内的功能,我们将含有FoxP2基因干扰序列的慢病毒立体定位注射到其中一种能够发出高频声波并能进行多普勒频移补偿行为的回声定位蝙蝠大蹄蝠的脑前扣带皮层(ACC)区域并成功建立了FoxP2基因knockdown的蝙蝠模型。我们又对FoxP2基因功能部分丧失后的动物个体进行了发声行为学研究。研究发现,FoxP2基因功能的丧失没有降低蝙蝠的高频发声频率,但增长了静息状态下的脉冲间隔时间。此外,FoxP2功能丧失后蝙蝠的多普勒频移补偿行为受到严重影响。多普勒频移补偿过程中的最大补偿深度和脉冲问隔时间在FoxP2功能丧失的动物个体中分别发生了显著的降低和增加。以上研究结果表明蝙蝠前扣带皮层区域表达的FoxP2基因在蝙蝠精确,快速的听觉-发声行为过程中扮演重要的角色。
2.miRNA是一类在真核生物中广泛存在的非编码小RNA,参与多种生物学过程。miRNA在产生过程中经过Drosha酶和Dicer酶的两次剪切,最终形成一个长度为22nt左右的miRNA成熟体,这类小RNA可以通过与RNA诱导的沉默复合体(RISC)结合并锚定到靶基因mRNA上根据序列互补配对情况对靶基因进行直接降解或翻译抑制,进而在转录后水平对靶基因的表达进行调控。miRNA能够对生理学过程进行有效微调并可以节省能量。近年来,miRNA的功能被人们高度关注,随着高通量测序方法的应用,越来越多物种的miRNA被测序鉴定出来。然而,哺乳动物翼手目蝙蝠类群的小RNA信息却仍是一片空白。本文成功构建了长翼蝠(Miniopterus fuliginosus)小RNA文库并进行高通量测序。通过将高通量测序结果与miRBase数据库中的己知脊椎动物miRNA比对并在相近蝙蝠物种莹鼠耳蝠(Myotis lucifugus)和马来大狐蝠(Pteropus vampyrus)的基因组中比对后,我们预测到338个保守miRNA (Conserved miRNA)成熟体组成了229个miRNA前体,并发现33个蝙蝠特异的miRNA (novel miRNA)。接下来,我们对长翼蝠保守miRNA序列的特征和变化进行了深入分析。研究发现,14个miRNA的“种子序列”发生了seed shifting。27个长翼蝠miRNA的碱基发生了突变(普通碱基突变,种子序列突变,插入或缺失)。根据miRNA前体在基因组上的位置信息和分布特点,我们发现有90个miRNA在基因组上成簇分布,分属于26个不同的基因簇。我们又对miRNA前体臂的使用做了深入研究,发现有5个miRNA前体发生了arm switching,7个miRNA前体臂发生了“无义反转”(使用与其他脊椎动物不同,但产生的成熟体序列是相同的)。为了研究在长翼蝠脑发育过程中参与的miRNA类群和功能。我们利用基因芯片对长翼蝠胚胎脑和成体脑的miRNA差异表达谱进行研究,发现有51个miRNA成熟体在胚胎脑和成体脑组织中有差异性的表达,说明这些miRNA在长翼蝠脑发育过程中起重要作用。我们的研究为深入了解长翼蝠miRNA的功能提供了基础并为研究蝙蝠脑发育的机制开辟了一条新的途径。
1. Forkhead box P2(FoxP2) is a member of the winged helix/forkhead class of transcription factors. Mutations of the FoxP2gene in human cause severe speech and language disorders. FoxP2is also found to be connected to song learning and adult song stability in songbird. Recently it has been shown that it underwent accelerated evolution in bats and may play a role in the evolution and development of echo location. To figure out the relevance between FoxP2and the complex high frequency vocal behavior of bat, we studied the difference of FoxP2expression in three echolocating bats(Hipposideros armiger, Rhinolophus ferrumequinum, and Myotis ricketti) and two non-echo locating bats (Rousettus leschenaultii and Cynopterus sphinx) at both mRNA and protein level, using in situ hybridization and immunohistochemistry. The results showed that the region of anterior cingulate cortex (ACC) exhibits a different FoxP2expression between the two kinds of bats. Then we report the loss of function study of FoxP2gene in bat brain tissue for the first time, based on RNAi mediated by lentivirus. We designed three shRNAs which can express short hairpin RNA (shRNA) targeting Hipposideros armiger FoxP2, one of the echolocating bats which can produce high frequency sound and perform Doppler-shift compensation (DSC). One of the three shRNAs was demonstrated to knock down FoxP2fusion protein efficiently in293T cell line. Then the pseudovirus particles that contain interference sequence were administered via stereotactic intracerebral microinjection into the anterior cingulate cortex of Hipposideros armiger to construct a FoxP2knockdown bat model. We examined the vocal behavior of FoxP2knockdown animals and found that they can still perform normal high frequency sound but the pulse interval at rest increased. Besides, knockdown of FoxP2expression in the ACC significantly altered DSC by decreasing the max compensation depth and increasing the pulse interval. Overall, the results suggest the expression of FoxP2 in ACC of Hipposideros armiger may play an important role in the precise, rapid audio-vocal integration and coordination.
2. MicroRNAs (miRNAs) are a class of endogenous small noncoding RNAs that widely exist in eukaryotic organism and play a key role in diverse biological processes. Mature miRNAs are generated through two sequential cleavages of the primary transcripts by Drosha and Dicer. This kind of small RNAs can integrate into RNA-induced silence complex (RISC) and regulate the target gene at post-transcriptional level either by inhibiting the mRNA translation or degrading the target gene directly according to the extent of base pairing. miRNA is a kind of fine-tuning RNA molecule that can regulate various functions. Recently, the solexa sequencing technology has become a convincing strategy for identifying miRNA transcriptome, more and more miRNAs were identified in different species. However, the miRNA informations of Chiroptera were still unknown. In this study, we constructed and sequenced a miRNA library from Miniopterus fuliginosus. We identified229miRNA precursors and338mature miRNAs (conserved miRNA) after aligning the sequencing data with known miRNAs registered in miRBase and the genome information of Myotis lucifugus and Pteropus vampyrus, two relatives of Miniopterus fuliginosus. We also discovered33bat specific novel miRNA precursors. Then we deeply analyzed the characteristics and variations of the conserved miRNAs. Among the total conserved miRNAs,14mature miRNAs have undergone seed shifting and27miRNAs have sequence changes (mutation, insert or delete). According to the genome loci of these miRNAs, we found90miRNAs distributed as gene clusters, belonging to26miRNA clusters. The arm usage was investigated and the results showed that5miRNAs occurred arm switching and7miRNAs had different arm usage compared to other vertebrates but failed to have any effect due to the mature miRNA sequences are identical ("nonsense switching").In addition, the expression patterns of miRNAs in embryo and adult brain were also investigated using comprehensive microarray profiling. Finally, we found51miRNAs showed a divergent expression pattern, which implied these miRNAs may play a role in brain development. The identification of miRNA transcriptome of Miniopterus fuliginosus definitely advances our knowledge of miRNA populations of bat and more importantly it would provide a clue for better understanding of their roles in brain development.
2.miRNA是一类在真核生物中广泛存在的非编码小RNA,参与多种生物学过程。miRNA在产生过程中经过Drosha酶和Dicer酶的两次剪切,最终形成一个长度为22nt左右的miRNA成熟体,这类小RNA可以通过与RNA诱导的沉默复合体(RISC)结合并锚定到靶基因mRNA上根据序列互补配对情况对靶基因进行直接降解或翻译抑制,进而在转录后水平对靶基因的表达进行调控。miRNA能够对生理学过程进行有效微调并可以节省能量。近年来,miRNA的功能被人们高度关注,随着高通量测序方法的应用,越来越多物种的miRNA被测序鉴定出来。然而,哺乳动物翼手目蝙蝠类群的小RNA信息却仍是一片空白。本文成功构建了长翼蝠(Miniopterus fuliginosus)小RNA文库并进行高通量测序。通过将高通量测序结果与miRBase数据库中的己知脊椎动物miRNA比对并在相近蝙蝠物种莹鼠耳蝠(Myotis lucifugus)和马来大狐蝠(Pteropus vampyrus)的基因组中比对后,我们预测到338个保守miRNA (Conserved miRNA)成熟体组成了229个miRNA前体,并发现33个蝙蝠特异的miRNA (novel miRNA)。接下来,我们对长翼蝠保守miRNA序列的特征和变化进行了深入分析。研究发现,14个miRNA的“种子序列”发生了seed shifting。27个长翼蝠miRNA的碱基发生了突变(普通碱基突变,种子序列突变,插入或缺失)。根据miRNA前体在基因组上的位置信息和分布特点,我们发现有90个miRNA在基因组上成簇分布,分属于26个不同的基因簇。我们又对miRNA前体臂的使用做了深入研究,发现有5个miRNA前体发生了arm switching,7个miRNA前体臂发生了“无义反转”(使用与其他脊椎动物不同,但产生的成熟体序列是相同的)。为了研究在长翼蝠脑发育过程中参与的miRNA类群和功能。我们利用基因芯片对长翼蝠胚胎脑和成体脑的miRNA差异表达谱进行研究,发现有51个miRNA成熟体在胚胎脑和成体脑组织中有差异性的表达,说明这些miRNA在长翼蝠脑发育过程中起重要作用。我们的研究为深入了解长翼蝠miRNA的功能提供了基础并为研究蝙蝠脑发育的机制开辟了一条新的途径。
1. Forkhead box P2(FoxP2) is a member of the winged helix/forkhead class of transcription factors. Mutations of the FoxP2gene in human cause severe speech and language disorders. FoxP2is also found to be connected to song learning and adult song stability in songbird. Recently it has been shown that it underwent accelerated evolution in bats and may play a role in the evolution and development of echo location. To figure out the relevance between FoxP2and the complex high frequency vocal behavior of bat, we studied the difference of FoxP2expression in three echolocating bats(Hipposideros armiger, Rhinolophus ferrumequinum, and Myotis ricketti) and two non-echo locating bats (Rousettus leschenaultii and Cynopterus sphinx) at both mRNA and protein level, using in situ hybridization and immunohistochemistry. The results showed that the region of anterior cingulate cortex (ACC) exhibits a different FoxP2expression between the two kinds of bats. Then we report the loss of function study of FoxP2gene in bat brain tissue for the first time, based on RNAi mediated by lentivirus. We designed three shRNAs which can express short hairpin RNA (shRNA) targeting Hipposideros armiger FoxP2, one of the echolocating bats which can produce high frequency sound and perform Doppler-shift compensation (DSC). One of the three shRNAs was demonstrated to knock down FoxP2fusion protein efficiently in293T cell line. Then the pseudovirus particles that contain interference sequence were administered via stereotactic intracerebral microinjection into the anterior cingulate cortex of Hipposideros armiger to construct a FoxP2knockdown bat model. We examined the vocal behavior of FoxP2knockdown animals and found that they can still perform normal high frequency sound but the pulse interval at rest increased. Besides, knockdown of FoxP2expression in the ACC significantly altered DSC by decreasing the max compensation depth and increasing the pulse interval. Overall, the results suggest the expression of FoxP2 in ACC of Hipposideros armiger may play an important role in the precise, rapid audio-vocal integration and coordination.
2. MicroRNAs (miRNAs) are a class of endogenous small noncoding RNAs that widely exist in eukaryotic organism and play a key role in diverse biological processes. Mature miRNAs are generated through two sequential cleavages of the primary transcripts by Drosha and Dicer. This kind of small RNAs can integrate into RNA-induced silence complex (RISC) and regulate the target gene at post-transcriptional level either by inhibiting the mRNA translation or degrading the target gene directly according to the extent of base pairing. miRNA is a kind of fine-tuning RNA molecule that can regulate various functions. Recently, the solexa sequencing technology has become a convincing strategy for identifying miRNA transcriptome, more and more miRNAs were identified in different species. However, the miRNA informations of Chiroptera were still unknown. In this study, we constructed and sequenced a miRNA library from Miniopterus fuliginosus. We identified229miRNA precursors and338mature miRNAs (conserved miRNA) after aligning the sequencing data with known miRNAs registered in miRBase and the genome information of Myotis lucifugus and Pteropus vampyrus, two relatives of Miniopterus fuliginosus. We also discovered33bat specific novel miRNA precursors. Then we deeply analyzed the characteristics and variations of the conserved miRNAs. Among the total conserved miRNAs,14mature miRNAs have undergone seed shifting and27miRNAs have sequence changes (mutation, insert or delete). According to the genome loci of these miRNAs, we found90miRNAs distributed as gene clusters, belonging to26miRNA clusters. The arm usage was investigated and the results showed that5miRNAs occurred arm switching and7miRNAs had different arm usage compared to other vertebrates but failed to have any effect due to the mature miRNA sequences are identical ("nonsense switching").In addition, the expression patterns of miRNAs in embryo and adult brain were also investigated using comprehensive microarray profiling. Finally, we found51miRNAs showed a divergent expression pattern, which implied these miRNAs may play a role in brain development. The identification of miRNA transcriptome of Miniopterus fuliginosus definitely advances our knowledge of miRNA populations of bat and more importantly it would provide a clue for better understanding of their roles in brain development.
引文
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