Developmental abnormalities in supporting cell phalangeal processes and cytoskeleton in the Gjb2 knockdown mouse model.
Developmental abnormalities in supporting cell phalangeal processes and cytoskeleton in the Gjb2 knockdown mouse model.
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Gjb2 敲低小鼠模型中支持细胞指骨过程和细胞骨架的发育异常。
DOI：
10.1242/dmm.033019
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发表时间：
2018-02-26
影响因子：
4.3
通讯作者：
Kong WJ
中科院分区：
文献类型：
--
作者：
Chen S;Xie L;Xu K;Cao HY;Wu X;Xu XX;Sun Y;Kong WJ
GJB2基因（编码连接蛋白26，即Cx26）的突变是人类遗传性听力损失最常见的病因，以往研究表明，在不同的Cx26基因敲除小鼠模型中，柯蒂氏器在出生后的发育停滞。为进一步探究这些小鼠耳蜗异常背后的病理变化及机制，我们通过在出生后第0天（P0）和第8天（P8）条件性敲低耳蜗Cx26，建立了转基因小鼠模型。在Cx26敲低18天后，记录听觉脑干反应，并分析柯蒂氏器的形态特征。P0敲低组小鼠在所有频率下均表现出严重听力损失，而P8敲低组小鼠听力近乎正常。P8敲低组中，柯蒂氏器结构正常，未观察到超微结构变化。P0敲低组中，外指细胞的指突未发育成指状结构，柱细胞中微管的形成显著减少；此外，柱细胞中乙酰化α - 微管蛋白的含量降低。我们的研究结果表明，Gjb2参与了柯蒂氏器结构成熟过程中柱细胞细胞骨架的出生后发育。在P0敲低小鼠中，柱细胞微管减少可能是导致柯蒂氏隧道无法打开的原因，而畸形的指突可能对柯蒂氏器的支撑框架产生负面影响，这可能是Gjb2相关听力损失的一种新机制。
总结：在柯蒂氏隧道开放前Cx26减少会阻碍支持细胞中微管的形成，这可能导致Gjb2敲低小鼠模型出现耳蜗发育异常和耳聋。
Mutations in the GJB2 gene [which encodes connexin 26 (Cx26)] are the most common causes of hereditary hearing loss in humans, and previous studies showed postnatal development arrest of the organ of Corti in different Cx26-null mouse models. To explore the pathological changes and the mechanism behind the cochlear abnormalities in these mice further, we established transgenic mouse models by conditional knockdown of cochlear Cx26 at postnatal day (P) 0 and P8. Auditory brainstem responses were recorded and the morphological features in the organ of Corti were analyzed 18 days after Cx26 knockdown. Mice in the P0 knockdown group displayed severe hearing loss at all frequencies, whereas mice in the P8 knockdown group showed nearly normal hearing. In the P8 knockdown group, the organ of Corti displayed normal architecture, and no ultrastructural changes were observed. In the P0 knockdown group, the phalangeal processes of Deiter's cells did not develop into finger-like structures, and the formation of microtubules in the pillar cells was significantly reduced; moreover, the amount of acetylated α-tubulin was reduced in pillar cells. Our results indicate that Gjb2 participates in postnatal development of the cytoskeleton in pillar cells during structural maturation of the organ of Corti. In P0 knockdown mice, the reduction in microtubules in pillar cells might be responsible for the failure of the tunnel of Corti to open, and the malformed phalangeal processes might negatively affect the supporting framework of the organ of Corti, which would be a new mechanism of Gjb2-related hearing loss. Summary: A reduction in connexin 26 before opening of the tunnel of Corti impedes microtubule formation in supporting cells, and this may lead to cochlear developmental abnormalities and deafness in the Gjb2 knockdown mouse model.
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DOI：
10.1016/j.bbrc.2009.05.023
发表时间：
2009-07-17
影响因子：
3.1
作者：
Wang, Yunfeng;Chang, Qing;Tang, Wenxue;Sun, Yu;Zhou, Binfei;Li, Huawei;Lin, Xi
通讯作者：
Lin, Xi
影响因子：
25
作者：
通讯作者：
--
DOI：
10.1152/physiol.00018.2009
发表时间：
2009-10
期刊：
Physiology (Bethesda, Md.)
影响因子：
--
作者：
Zdebik AA;Wangemann P;Jentsch TJ
通讯作者：
Jentsch TJ
DOI：
10.1023/b:neur.0000005602.18713.02
发表时间：
2003-02-01
期刊：
JOURNAL OF NEUROCYTOLOGY
影响因子：
--
作者：
Jensen-Smith, HC;Eley, J;Hallworth, R
通讯作者：
Hallworth, R
DOI：
10.1007/bf00186783
发表时间：
1995-02-01
期刊：
ANATOMY AND EMBRYOLOGY
影响因子：
--
作者：
KIKUCHI, T;KIMURA, RS;ADAMS, JC
通讯作者：
ADAMS, JC