增龄相关听力损失小鼠耳蜗和蜗神经核MeCP2、BDNF、Atoh1基因表达的初步研究
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摘要
目的:本研究在对不同月龄BALB/c小鼠听功能和耳蜗形态学研究的基础上,通过检测不同月龄小鼠耳蜗和蜗神经核中MeCP2、BDNF和Atoh1基因的表达特点,初步探讨其在年龄相关性听力损失中的作用,为进一步确定听觉老化的相关基因,探讨老年性耳聋发病的分子机制打下基础。
方法:①通过听性脑干反应(ABR)测试、耳蜗毛细胞铺片/计数及扫描电镜等方法,对3、6、12和18月龄组小鼠8 kHz听反应阈及耳蜗毛细胞缺失和Corti器形态学变化进行对比研究。②应用免疫组化技术,检测不同月龄组小鼠耳蜗和蜗神经核组织中MeCP2蛋白的表达与分布情况。③应用Western blot技术,检测各月龄组小鼠耳蜗和蜗神经核中MeCP2的蛋白表达水平。④应用荧光定量逆转录多聚酶链反应(RT-PCR),对各月龄组小鼠耳蜗和蜗神经核中MeCP2、BDNF和Atoh1基因的mRNA表达水平进行检测。
结果:①ABR检测显示3、6和12月龄组小鼠8 kHz听反应阂分别为(25±5.1)、(52±6.7)、(93±7.5)dB SPL,18月龄组120 dBSPL刺激声基本测不出听觉反应。耳蜗铺片毛细胞计数自6月龄组外毛细胞出现显著缺失,随月龄增加而加重,由底回逐渐向项回发展,至12月龄时耳蜗底回和中回外毛细胞几乎完全丧失,内毛细胞显著缺失。扫描电镜显示6月龄组小鼠耳蜗毛细胞静纤毛可见不同程度的缺失、转位、散乱、倒伏、融合、变短现象,随月龄增加而逐渐加重。②免疫组化染色:MeCP2蛋白在BALB/c小鼠耳蜗和蜗神经核中均有表达,主要为细胞核着色,随月龄增长,小鼠耳蜗和蜗神经核染色阳性程度变弱。③Western blot检测:四个不同月龄组小鼠耳蜗和蜗神经核组织中MeCP2蛋白表达浓度随年龄增长而减弱。④RT-PCR分析:MeCP2、BDNF和Atoh1基因的mRNA表达水平均随月龄增长逐渐下降。6、12、18月龄组mRNA及蛋白的表达的光密度比值明显低于3月龄组,各组间比较有统计学显著差异(P＜0.01)。PCR产物测序及BLAST比较分析证实RT-PCR产物与目的基因mRNA序列完全一致。
结论:①BALB/c小鼠听力损失、耳蜗毛细胞缺失和纤毛损害随年龄增长而逐渐加重。②MeCP2在小鼠耳蜗和蜗神经核组织中均有表达,主要表现为核表达,其表达水平呈增龄相关性减弱。③小鼠耳蜗和蜗神经核中MeCP2、BDNF、Atoh1基因mRNA表达水平随月龄增长而逐渐降低,三种基因的表达水平呈显著一致性。④MeCP2及其相关基因BDNF和Atoh1表现出增龄相关性表达减弱,它们可能在老年性耳聋的发病机制中起重要作用。
Objective:On the basis of auditory function measurements and cochlear morphological evaluation in BALB/c mice with different ages, in the present study,we attempt to investigate the characteristics of methyl-CpG-binding protein 2(MeCP2),brain-derived neurotrophic factor(BDNF) and atonal homolog 1(Atoh1) expressions in the cochlea and cochlear nuclei of BALB/c mice with different ages,so as to explore the possible roles of these genes on age-related hearing loss,and to lay a foundation for further analyzing the aging-related genes of auditory system and finding the molecular mechanisms of presbycusis.
Method:①Through auditory brain stem response(ABR) measurements,cochlear surface preparation/hair cell counting and scanning electronic microscopy,the 8 kHz auditory thresholds,hair cell losses and morphological changes of organ of Corti were comparatively investigated in 3-,6-,12- and 18-month-old BALB/c mice.②The expression and distribution of MeCP2 protein in the cochlea and cochlear nuclei of BALB/c mice with different ages were detected and analyzed by means of immunohistochemical staining.③The levels of MeCP2 protein in the cochlea and cochlear nuclei of mice with different ages were detected and analyzed via Western blot assay.④Detection and analysis of the mRNA expression of MeCP2,BDNF and Atoh1 in the cochlea and cochlear nuclei were carryied out by RT-PCR on 3-,6-,12- and 18-month- old mice,respectively.
Results:①ABR measurements demonstrated that auditory thresholds at 8 kHz in 3-,6- and 12-month-old mice were(25±5.1), (52±6.7) and(93±7.5) dB SPL,respectively.In eighteen-month-old mice, the 8 kHz auditory responses at 120 dB SPL could almost not be dectected.The outer hair cell(OHC) loss was mainly observed in the basal turn of the cochlea in 6-month-old mice and got deteriorated with increase of age.In 12-month-old mice,the whole OHCs were almost absent at basal and middle turn,and inner hair cells(IHC) were markedly missing.Scanning electronic microscopy showed that ultrastructural characteristics of the stereocilia On the outer and inner hair cells were short and disarrayed bundles,hair fusion and stereocilia bundles loss. These changes got aggravated with aging.②Immunohistochemical staining showed that MeCP2 expressed in both cochlea and cochlear nuclei of BALB/c mice,predominantly expressing in the cell nuclei.The positive staining became weaker following the age increase.③Western blot assay showed that the levels of MeCP2 protein in the cochlea and cochlear nuclei tissues of mice decreased with aging.④Results of RT-PCR demonstrated that the mRNA expression of MeCP2,BDNF and Atohl decreased as the age increasing.The optical density(OD) ratio of MeCP2,BDNF and Atoh1 was significantly lower in 6-,12- and 18-month-old mice than in 3-month-old mice.Statistics analysis showed that the mRNA expression between each two groups had a significant difference(p＜0.01).Furthermore,it was verified that the gene sequence of mRNA was identical to that of RT-PCR by PCR and BLAST.
Conclusion:①Hearing loss,hair cell missing and stereocilia bundle damage in BALB/c mice gradually become heavier with aging.②MeCP2 was expressed both in mouse cochlea and cochlear nuclei,predominantly expressing in cell nuclei,and the expression levels age-relatedly decreased.③The mRNA expression of MeCP2,BDNF and Atoh1 gradually decreased as the age increasing.The expression of those three genes was highly consistent.④Expression of MeCP2 and its related genes,BDNF and Atoh1,decrease following the age increasing, indicating that they may play an immportant role in the development of age-related hearing loss.
方法:①通过听性脑干反应(ABR)测试、耳蜗毛细胞铺片/计数及扫描电镜等方法,对3、6、12和18月龄组小鼠8 kHz听反应阈及耳蜗毛细胞缺失和Corti器形态学变化进行对比研究。②应用免疫组化技术,检测不同月龄组小鼠耳蜗和蜗神经核组织中MeCP2蛋白的表达与分布情况。③应用Western blot技术,检测各月龄组小鼠耳蜗和蜗神经核中MeCP2的蛋白表达水平。④应用荧光定量逆转录多聚酶链反应(RT-PCR),对各月龄组小鼠耳蜗和蜗神经核中MeCP2、BDNF和Atoh1基因的mRNA表达水平进行检测。
结果:①ABR检测显示3、6和12月龄组小鼠8 kHz听反应阂分别为(25±5.1)、(52±6.7)、(93±7.5)dB SPL,18月龄组120 dBSPL刺激声基本测不出听觉反应。耳蜗铺片毛细胞计数自6月龄组外毛细胞出现显著缺失,随月龄增加而加重,由底回逐渐向项回发展,至12月龄时耳蜗底回和中回外毛细胞几乎完全丧失,内毛细胞显著缺失。扫描电镜显示6月龄组小鼠耳蜗毛细胞静纤毛可见不同程度的缺失、转位、散乱、倒伏、融合、变短现象,随月龄增加而逐渐加重。②免疫组化染色:MeCP2蛋白在BALB/c小鼠耳蜗和蜗神经核中均有表达,主要为细胞核着色,随月龄增长,小鼠耳蜗和蜗神经核染色阳性程度变弱。③Western blot检测:四个不同月龄组小鼠耳蜗和蜗神经核组织中MeCP2蛋白表达浓度随年龄增长而减弱。④RT-PCR分析:MeCP2、BDNF和Atoh1基因的mRNA表达水平均随月龄增长逐渐下降。6、12、18月龄组mRNA及蛋白的表达的光密度比值明显低于3月龄组,各组间比较有统计学显著差异(P＜0.01)。PCR产物测序及BLAST比较分析证实RT-PCR产物与目的基因mRNA序列完全一致。
结论:①BALB/c小鼠听力损失、耳蜗毛细胞缺失和纤毛损害随年龄增长而逐渐加重。②MeCP2在小鼠耳蜗和蜗神经核组织中均有表达,主要表现为核表达,其表达水平呈增龄相关性减弱。③小鼠耳蜗和蜗神经核中MeCP2、BDNF、Atoh1基因mRNA表达水平随月龄增长而逐渐降低,三种基因的表达水平呈显著一致性。④MeCP2及其相关基因BDNF和Atoh1表现出增龄相关性表达减弱,它们可能在老年性耳聋的发病机制中起重要作用。
Objective:On the basis of auditory function measurements and cochlear morphological evaluation in BALB/c mice with different ages, in the present study,we attempt to investigate the characteristics of methyl-CpG-binding protein 2(MeCP2),brain-derived neurotrophic factor(BDNF) and atonal homolog 1(Atoh1) expressions in the cochlea and cochlear nuclei of BALB/c mice with different ages,so as to explore the possible roles of these genes on age-related hearing loss,and to lay a foundation for further analyzing the aging-related genes of auditory system and finding the molecular mechanisms of presbycusis.
Method:①Through auditory brain stem response(ABR) measurements,cochlear surface preparation/hair cell counting and scanning electronic microscopy,the 8 kHz auditory thresholds,hair cell losses and morphological changes of organ of Corti were comparatively investigated in 3-,6-,12- and 18-month-old BALB/c mice.②The expression and distribution of MeCP2 protein in the cochlea and cochlear nuclei of BALB/c mice with different ages were detected and analyzed by means of immunohistochemical staining.③The levels of MeCP2 protein in the cochlea and cochlear nuclei of mice with different ages were detected and analyzed via Western blot assay.④Detection and analysis of the mRNA expression of MeCP2,BDNF and Atoh1 in the cochlea and cochlear nuclei were carryied out by RT-PCR on 3-,6-,12- and 18-month- old mice,respectively.
Results:①ABR measurements demonstrated that auditory thresholds at 8 kHz in 3-,6- and 12-month-old mice were(25±5.1), (52±6.7) and(93±7.5) dB SPL,respectively.In eighteen-month-old mice, the 8 kHz auditory responses at 120 dB SPL could almost not be dectected.The outer hair cell(OHC) loss was mainly observed in the basal turn of the cochlea in 6-month-old mice and got deteriorated with increase of age.In 12-month-old mice,the whole OHCs were almost absent at basal and middle turn,and inner hair cells(IHC) were markedly missing.Scanning electronic microscopy showed that ultrastructural characteristics of the stereocilia On the outer and inner hair cells were short and disarrayed bundles,hair fusion and stereocilia bundles loss. These changes got aggravated with aging.②Immunohistochemical staining showed that MeCP2 expressed in both cochlea and cochlear nuclei of BALB/c mice,predominantly expressing in the cell nuclei.The positive staining became weaker following the age increase.③Western blot assay showed that the levels of MeCP2 protein in the cochlea and cochlear nuclei tissues of mice decreased with aging.④Results of RT-PCR demonstrated that the mRNA expression of MeCP2,BDNF and Atohl decreased as the age increasing.The optical density(OD) ratio of MeCP2,BDNF and Atoh1 was significantly lower in 6-,12- and 18-month-old mice than in 3-month-old mice.Statistics analysis showed that the mRNA expression between each two groups had a significant difference(p＜0.01).Furthermore,it was verified that the gene sequence of mRNA was identical to that of RT-PCR by PCR and BLAST.
Conclusion:①Hearing loss,hair cell missing and stereocilia bundle damage in BALB/c mice gradually become heavier with aging.②MeCP2 was expressed both in mouse cochlea and cochlear nuclei,predominantly expressing in cell nuclei,and the expression levels age-relatedly decreased.③The mRNA expression of MeCP2,BDNF and Atoh1 gradually decreased as the age increasing.The expression of those three genes was highly consistent.④Expression of MeCP2 and its related genes,BDNF and Atoh1,decrease following the age increasing, indicating that they may play an immportant role in the development of age-related hearing loss.
引文
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