Timed conditional null of connexin26 in mice reveals temporary requirements of connexin26 in key cochlear developmental events before the onset of hearing
Timed conditional null of connexin26 in mice reveals temporary requirements of connexin26 in key cochlear developmental events before the onset of hearing
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DOI：
10.1016/j.nbd.2014.09.005
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发表时间：
2015-01-01
影响因子：
6.1
通讯作者：
Lin, Xi
中科院分区：
文献类型：
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作者：
Chang, Qing;Tang, Wenxue;Lin, Xi
编码间隙连接蛋白连接蛋白26（Cx26）的Gjb2基因突变是人类遗传性耳聋的最常见形式，在许多种族人群中占非综合征性先天性耳聋病例的一半左右。成熟耳蜗中的钾离子（K+）再循环是正常听力所必需的。据认为，间隙连接是必不可少的K+循环和Gjb2突变导致Gjb2相关的耳聋破坏K+循环在成熟的耳蜗。在这里，我们提出的证据表明，Gjb2是所需的正常发展的新生儿器官的Corti之前，在小鼠的听力发作。在条件性Gjb2 null（cCx26 null）小鼠中，内毛细胞中的带状突触仍然发育不良，I型传入纤维未能完成细化过程以形成对单个内毛细胞的会聚神经支配。支持细胞的自发去极化活动，通常减少野生型耳蜗出生后第8天（P8）后，在P8后的突变小鼠的耳蜗仍然很强。此外，耳聋表型很容易产生，只有当Cx26的表达在Corti器官显着降低P6前。在更成熟的耳蜗中，类似数量的Cx26减少对听力敏感性的损害作用要弱得多。我们的研究结果表明，Cx26在Corti器官的成熟过程中起着至关重要的作用，在建立高K+的内淋巴和听力发作之前。这些结果表明，Cx26耳聋的成功治疗需要在耳蜗完全成熟之前进行早期干预。(C)2015 Elsevier Inc. All rights reserved.
Mutations in the Gjb2 gene, which encodes a gap junction protein connexin26 (Cx26), are the most prevalent form of hereditary deafness in humans and represent about half of non-syndromic congenital deafness cases in many ethnic populations. Cochlear potassium (K+) recycling in mature cochlea is required for normal hearing. It is thought that gap junctions are essential for K+ recycling and that Gjb2 mutations cause Gjb2-associated deafness by disrupting K+ recycling in mature cochlea. Here we present evidence showing that Gjb2 is required for normal development of the neonatal organ of Corti prior to the onset of the hearing in mice. In the conditional Gjb2 null (cCx26 null) mice, ribbon synapses in inner hair cells remained poorly developed, the afferent type I fibers failed to finish the refinement process to form convergent innervation to individual inner hair cells. The spontaneous depolarizing activities in the supporting cells, which normally diminish in the wild type cochleae after postnatal day 8 (P8), remained strong in the cochlea after P8 in the mutant mice. Furthermore, the deafness phenotype was readily generated only if the Cx26 expression in the organ of Corti was significantly reduced before P6. Similar amount of Cx26 reduction in more mature cochleae had a much weaker effect in damaging the hearing sensitivity. Our findings indicated that Cx26 plays essential roles in the maturation process of the organ of Corti prior to the establishment of high K+ in the endolymph and the onset of hearing. These results suggest that successful treatment of Cx26 deafness requires early intervention before the cochlea fully matures. (C) 2015 Elsevier Inc. All rights reserved.