Balance and hearing deficits in mice with a null mutation in the gene encoding plasma membrane Ca2+-ATPase isoform 2
Balance and hearing deficits in mice with a null mutation in the gene encoding plasma membrane Ca2+-ATPase isoform 2
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DOI：
10.1074/jbc.273.30.18693
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发表时间：
1998-07-24
影响因子：
4.8
通讯作者：
Shull, GE
中科院分区：
文献类型：
--
作者：
Kozel, PJ;Friedman, RA;Shull, GE
质膜Ca ~（2+）-ATP酶亚型2（PMCA_2）在耳蜗外毛细胞和螺旋神经节细胞中的高表达表明其在听觉中的独特作用。为了分析PMCA 2的生理作用，我们使用基因靶向来产生PMCA 2缺陷小鼠，杂合小鼠的育种产生了活的纯合突变后代。PMCA 2-null小鼠比杂合和野生型小鼠生长更慢，并且表现出不稳定的步态和维持平衡的困难。对突变型和野生型小鼠的小脑和内耳的组织学分析显示，无效突变体的浦肯野神经元数量略有增加（其中PMCA 2高度表达），分子层厚度减少，前庭系统中没有耳石，以及Corti器官的一系列异常。听觉诱发脑干反应的分析显示，纯合子突变体是耳聋的，杂合子小鼠有显着的听力损失。这些数据表明，PMCA 2是平衡和听力所必需的，并表明它可能是用于耳石形成和维持的钙的主要来源。
Plasma membrane Ca2+-ATPase isoform 2 (PMCA2) exhibits a highly restricted tissue distribution, suggesting that it serves more specialized physiological functions than some of the other isoforms, A unique role in hearing is indicated by the high levels of PMCA2 expression in cochlear outer hair cells and spiral ganglion cells. To analyze the physiological role of PMCA2 we used gene targeting to produce PMCA2-deficient mice, Breeding of heterozygous mice yielded live homozygous mutant offspring. PMCA2-null mice grow more slowly than heterozygous and wild-type mice and exhibit an unsteady gait and difficulties in maintaining balance. Histological analysis of the cerebellum and inner ear of mutant and wild-type mice revealed that null mutants had slightly increased numbers of Purkinje neurons tin which PMCA2 is highly expressed), a decreased thickness of the molecular layer, an absence of otoconia in the vestibular system, and a range of abnormalities of the organ of Corti. Analysis of auditory evoked brainstem responses revealed that homozygous mutants were deaf and that heterozygous mice had a significant hearing loss. These data demonstrate that PMCA2 is required for both balance and hearing and suggest that it may be a major source of the calcium used in the formation and maintenance of otoconia.