Loss of Baiap2l2 destabilizes the transducing stereocilia of cochlear hair cells and leads to deafness.
Loss of Baiap2l2 destabilizes the transducing stereocilia of cochlear hair cells and leads to deafness.
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DOI：
10.1113/jp280670
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Marcotti W
中科院分区：
文献类型：
--
作者：
Carlton AJ;Halford J;Underhill A;Jeng JY;Avenarius MR;Gilbert ML;Ceriani F;Ebisine K;Brown SDM;Bowl MR;Barr-Gillespie PG;Marcotti W
听毛细胞的机械电转导需要高度专业化的静纤毛束，从其顶面的项目，形成一个特点分级的“楼梯”结构。这些静纤毛束的形态发生和维持是一个严格调控的过程，需要几种肌动蛋白结合蛋白的参与，其中许多仍然是未知的。我们鉴定了一种新的静纤毛蛋白，I-BAR蛋白BAIAP 2L 2，它定位于内毛细胞和外毛细胞（IHC和OHC）中较短的转导静纤毛的尖端。我们发现，Baiap 2l 2缺陷小鼠失去了他们的第二和第三行静纤毛，他们的机电换能器电流，并发展为进行性听力损失，成为耳聋的8个月大。我们证明，BAIAP 2L 2定位到静纤毛尖端依赖于马达蛋白MYO 15 A及其货物EPS 8。我们认为BAIAP 2L 2是一个新的关键蛋白，它在成熟耳蜗毛细胞中维持着转导静纤毛的功能。声波到电信号的转换依赖于机械敏感的静纤毛束，从耳蜗内的毛细胞的顶面突出。这些基于肌动蛋白的静纤毛的高度和宽度在整个生命过程中受到严格调节，以建立和维持其特征性的阶梯状结构，这对于正常的机械电转导至关重要。在这里，我们表明BAIAP 2L 2，I-BAR蛋白家族的成员，是一种新鉴定的毛束蛋白，定位于小鼠耳蜗毛细胞中转导静纤毛的短行尖端。BAIAP 2L 2从出生后第2.5天（P2.5）开始在整个成年期通过免疫组织化学检测。在Baiap 2l 2缺陷小鼠中，外毛细胞（OHC），而不是内毛细胞（IHC），开始失去它们的第三排静纤毛，并显示出从P9后的机电换能器电流的大小减少。在接下来的听力后几周内，束的有序楼梯结构逐渐恶化，以至于到8个月大时，Baiap 2l 2缺陷小鼠的OHC和IHC都失去了大部分第二和第三行静纤毛并变得耳聋。我们还发现BAIAP 2L 2与其他参与正常毛束形态发生的关键立体纤毛蛋白相互作用，如CDC 42，RAC 1，EPS 8和ESPNL。此外，我们表明，BAIAP 2L 2定位到静纤毛尖端取决于马达蛋白MYO 15 A和其货物EPS 8。我们建议，BAIAP 2L 2是关键的转导静纤毛在成熟的小鼠耳蜗毛细胞的正常肌动蛋白结构的维护。听毛细胞的机械电转导需要高度专业化的静纤毛束，从其顶面的项目，形成一个特点分级的“楼梯”结构。这些静纤毛束的形态发生和维持是一个严格调控的过程，需要几种肌动蛋白结合蛋白的参与，其中许多仍然是未知的。我们鉴定了一种新的静纤毛蛋白，I-BAR蛋白BAIAP 2L 2，它定位于内毛细胞和外毛细胞（IHC和OHC）中较短的转导静纤毛的尖端。我们发现，Baiap 2l 2缺陷小鼠失去了他们的第二和第三行静纤毛，他们的机电换能器电流，并发展为进行性听力损失，成为耳聋的8个月大。我们证明，BAIAP 2L 2定位到静纤毛尖端依赖于马达蛋白MYO 15 A及其货物EPS 8。我们认为BAIAP 2L 2是一个新的关键蛋白，它在成熟耳蜗毛细胞中维持着转导静纤毛的功能。
Mechanoelectrical transduction at auditory hair cells requires highly specialized stereociliary bundles that project from their apical surface, forming a characteristic graded ‘staircase’ structure. The morphogenesis and maintenance of these stereociliary bundles is a tightly regulated process requiring the involvement of several actin‐binding proteins, many of which are still unidentified. We identify a new stereociliary protein, the I‐BAR protein BAIAP2L2, which localizes to the tips of the shorter transducing stereocilia in both inner and outer hair cells (IHCs and OHCs). We find that Baiap2l2 deficient mice lose their second and third rows of stereocilia, their mechanoelectrical transducer current, and develop progressive hearing loss, becoming deaf by 8 months of age. We demonstrate that BAIAP2L2 localization to stereocilia tips is dependent on the motor protein MYO15A and its cargo EPS8. We propose that BAIAP2L2 is a new key protein required for the maintenance of the transducing stereocilia in mature cochlear hair cells. The transduction of sound waves into electrical signals depends upon mechanosensitive stereociliary bundles that project from the apical surface of hair cells within the cochlea. The height and width of these actin‐based stereocilia is tightly regulated throughout life to establish and maintain their characteristic staircase‐like structure, which is essential for normal mechanoelectrical transduction. Here, we show that BAIAP2L2, a member of the I‐BAR protein family, is a newly identified hair bundle protein that is localized to the tips of the shorter rows of transducing stereocilia in mouse cochlear hair cells. BAIAP2L2 was detected by immunohistochemistry from postnatal day 2.5 (P2.5) throughout adulthood. In Baiap2l2 deficient mice, outer hair cells (OHCs), but not inner hair cells (IHCs), began to lose their third row of stereocilia and showed a reduction in the size of the mechanoelectrical transducer current from just after P9. Over the following post‐hearing weeks, the ordered staircase structure of the bundle progressively deteriorates, such that, by 8 months of age, both OHCs and IHCs of Baiap2l2 deficient mice have lost most of the second and third rows of stereocilia and become deaf. We also found that BAIAP2L2 interacts with other key stereociliary proteins involved in normal hair bundle morphogenesis, such as CDC42, RAC1, EPS8 and ESPNL. Furthermore, we show that BAIAP2L2 localization to the stereocilia tips depends on the motor protein MYO15A and its cargo EPS8. We propose that BAIAP2L2 is key to maintenance of the normal actin structure of the transducing stereocilia in mature mouse cochlear hair cells. Mechanoelectrical transduction at auditory hair cells requires highly specialized stereociliary bundles that project from their apical surface, forming a characteristic graded ‘staircase’ structure. The morphogenesis and maintenance of these stereociliary bundles is a tightly regulated process requiring the involvement of several actin‐binding proteins, many of which are still unidentified. We identify a new stereociliary protein, the I‐BAR protein BAIAP2L2, which localizes to the tips of the shorter transducing stereocilia in both inner and outer hair cells (IHCs and OHCs). We find that Baiap2l2 deficient mice lose their second and third rows of stereocilia, their mechanoelectrical transducer current, and develop progressive hearing loss, becoming deaf by 8 months of age. We demonstrate that BAIAP2L2 localization to stereocilia tips is dependent on the motor protein MYO15A and its cargo EPS8. We propose that BAIAP2L2 is a new key protein required for the maintenance of the transducing stereocilia in mature cochlear hair cells.
影响因子：
3.7
作者：
Olt J;Mburu P;Johnson SL;Parker A;Kuhn S;Bowl M;Marcotti W;Brown SD
通讯作者：
Brown SD