Mutant analysis reveals whirlin as a dynamic organizer in the growing hair cell stereocilium
Mutant analysis reveals whirlin as a dynamic organizer in the growing hair cell stereocilium
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DOI：
10.1093/hmg/ddi035
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发表时间：
2005-02-01
影响因子：
3.5
通讯作者：
Brown, SDM
中科院分区：
文献类型：
--
作者：
Kikkawa, Y;Mburu, P;Brown, SDM
对于导致内耳毛细胞表面静纤毛生长的分子过程知之甚少。已知PDZ蛋白whirlin通过whirler突变参与哺乳动物感觉毛细胞中的静纤毛伸长和肌动蛋白聚合过程。我们使用相关的小鼠突变体研究了回旋蛋白及其假定的相互作用伙伴肌球蛋白 XVa 在静纤毛中的功能。我们提出了一种抗体，可以检测回旋蛋白的短亚型，该抗体已被证明可以挽救回旋突变体中的静纤毛生长缺陷。我们表明，旋转体定位于静纤毛的尖端。在静纤毛生长过程中，whirlin 的表达是动态的，表现出静纤毛行的有序外观和淡出，并揭示了穿过静纤毛束的过程的新颖分子分级。内毛细胞中的回旋信号先于外毛细胞逐渐消失，这与内毛细胞静纤毛的较早成熟一致。在静纤毛缩短的肌球蛋白 XVa 突变体中，静纤毛尖端中的回旋蛋白表达停滞并加速淡出。在回旋蛋白突变体中，肌球蛋白 XVa 仍然在静纤毛中表达，但其在静纤毛尖端的出现被延迟。数据表明，whirlin 表达是静纤毛伸长和肌动蛋白聚合的关键和动态组织者。
Little is known of the molecular processes that lead to the growth of stereocilia on the surface of hair cells in the inner ear. The PDZ protein whirlin is known, by virtue of the whirler mutation, to be involved in the process of stereocilia elongation and actin polymerization in the sensory hair cells of mammals. We have investigated the function of whirlin and its putative interacting partner, myosin XVa, in the stereocilium using relevant mice mutants. We raised an antibody that detects the short isoform of the whirlin protein which has been demonstrated to rescue the stereocilia growth defect in the whirler mutant. We show that whirlin localizes at the tips of stereocilia. Expression of whirlin is dynamic during stereocilia growth, demonstrating an ordered appearance and fade-out across the stereocilia rows and revealing a novel molecular gradation of process traversing the stereocilia bundle. Fade-out of whirlin in inner hair cells precedes that of outer hair cells, consistent with the earlier maturation of inner hair cell stereocilia. In myosin XVa mutants in which stereocilia are shortened, whirlin expression in the stereocilia tips is stalled and fade-out is accelerated. In whirlin mutants, myosin XVa is still expressed in stereocilia, but its appearance at the stereocilia tip is delayed. The data indicate that whirlin expression is a critical and dynamic organizer for stereocilia elongation and actin polymerization.