Deficiency of transcription factor Brn4 disrupts cochlear gap junction plaques in a model of DFN3 non-syndromic deafness.
Deficiency of transcription factor Brn4 disrupts cochlear gap junction plaques in a model of DFN3 non-syndromic deafness.
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DOI：
10.1371/journal.pone.0108216
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kamiya K
中科院分区：
文献类型：
--
作者：
Kidokoro Y;Karasawa K;Minowa O;Sugitani Y;Noda T;Ikeda K;Kamiya K
Brn4编码一种POU转录因子，是导致DFN3的基因，DFN3是一种X染色体连锁的非综合征型听力损失。Brn4基因缺陷小鼠具有低耳蜗内电位(EP)、听力损失和螺旋韧带纤维细胞超微结构改变，但Brn4缺乏导致低EP的分子病理机制尚不清楚。Gjb2和Gjb6基因分别编码缝隙连接蛋白Cx26(Cx26)和Cx30(Cx30)基因，这两个基因分别编码缝隙连接蛋白，并在耳蜗纤维细胞和非感觉上皮细胞(即耳蜗支持细胞)中表达，以维持适当的EP，这与遗传性感音神经性耳聋有关。已有的假设是，耳蜗区的缝隙连接提供了一条细胞间通道，K+通过该通道运输，以维持感觉毛细胞兴奋所需的高水平的EP。在这里，我们用共聚焦显微镜和三维图形重建技术分析了Brn4基因缺陷小鼠不同发育阶段耳蜗区支持细胞缝隙连接斑块的形成。对照组小鼠的缝隙连接主要由Cx26和Cx30组成，沿着细胞-细胞连接部位与相邻细胞形成线状斑块。这些斑块形成正常内沟细胞和边缘细胞的五角形或六角形轮廓。然而，Brn4缺陷小鼠的缝隙连接斑块并没有显示出正常的线性结构，而是在细胞-细胞连接位置周围形成了小斑点。Brn4基因缺陷小鼠的缝隙连接长度显著缩短，Cx26和Cx30水平显著降低。因此，Brn4突变影响了缝隙连接蛋白在耳蜗支持细胞边缘的组装和定位，这表明Brn4在很大程度上有助于耳蜗缝隙连接特性，以维持耳蜗适当的EP，类似于连接蛋白相关性耳聋。
Brn4, which encodes a POU transcription factor, is the gene responsible for DFN3, an X chromosome–linked, non-syndromic type of hearing loss. Brn4-deficient mice have a low endocochlear potential (EP), hearing loss, and ultrastructural alterations in spiral ligament fibrocytes, however the molecular pathology through which Brn4 deficiency causes low EP is still unclear. Mutations in the Gjb2 and Gjb6 genes encoding the gap junction proteins connexin26 (Cx26) and connexin30 (Cx30) genes, respectively, which encode gap junction proteins and are expressed in cochlear fibrocytes and non-sensory epithelial cells (i.e., cochlear supporting cells) to maintain the proper EP, are responsible for hereditary sensorineural deafness. It has been hypothesized that the gap junction in the cochlea provides an intercellular passage by which K+ is transported to maintain the EP at the high level necessary for sensory hair cell excitation. Here we analyzed the formation of gap junction plaques in cochlear supporting cells of Brn4-deficient mice at different stages by confocal microscopy and three-dimensional graphic reconstructions. Gap junctions from control mice, which are composed mainly of Cx26 and Cx30, formed linear plaques along the cell-cell junction sites with adjacent cells. These plaques formed pentagonal or hexagonal outlines of the normal inner sulcus cells and border cells. Gap junction plaques in Brn4-deficient mice did not, however, show the normal linear structure but instead formed small spots around the cell-cell junction sites. Gap junction lengths were significantly shorter, and the level of Cx26 and Cx30 was significantly reduced in Brn4-deficient mice compared with littermate controls. Thus the Brn4 mutation affected the assembly and localization of gap junction proteins at the cell borders of cochlear supporting cells, suggesting that Brn4 substantially contributes to cochlear gap junction properties to maintain the proper EP in cochleae, similar to connexin-related deafness.
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影响因子：
4
作者：
Gilleron, Jerome;Fiorini, Celine;Pointis, Georges
通讯作者：
Pointis, Georges
影响因子：
158.5
作者：
del Castillo, I;Villamar, M;Moreno, F
通讯作者：
Moreno, F
DOI：
10.1016/s0006-291x(03)01166-5
发表时间：
2003-07-25
影响因子：
3.1
作者：
Ahmad, S;Chen, SP;Lin, X
通讯作者：
Lin, X
影响因子：
4.6
作者：
Trowe, Mark-Oliver;Maier, Hannes;Kispert, Andreas
通讯作者：
Kispert, Andreas
影响因子：
5.3
作者：
Delprat, B;Ruel, J;Hamel, CP
通讯作者：
Hamel, CP