School of Biosciences, University of Sheffield, Sheffield, UK.
Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
EMBO J. 2023 Feb 15;42(4):e112118. doi: 10.15252/embj.2022112118. Epub 2023 Jan 3.
Sensory-independent Ca spiking regulates the development of mammalian sensory systems. In the immature cochlea, inner hair cells (IHCs) fire spontaneous Ca action potentials (APs) that are generated either intrinsically or by intercellular Ca waves in the nonsensory cells. The extent to which either or both of these Ca signalling mechansims are required for IHC maturation is unknown. We find that intrinsic Ca APs in IHCs, but not those elicited by Ca waves, regulate the maturation and maintenance of the stereociliary hair bundles. Using a mouse model in which the potassium channel Kir2.1 is reversibly overexpressed in IHCs (Kir2.1-OE), we find that IHC membrane hyperpolarization prevents IHCs from generating intrinsic Ca APs but not APs induced by Ca waves. Absence of intrinsic Ca APs leads to the loss of mechanoelectrical transduction in IHCs prior to hearing onset due to progressive loss or fusion of stereocilia. RNA-sequencing data show that pathways involved in morphogenesis, actin filament-based processes, and Rho-GTPase signaling are upregulated in Kir2.1-OE mice. By manipulating in vivo expression of Kir2.1 channels, we identify a "critical time period" during which intrinsic Ca APs in IHCs regulate hair-bundle function.
感觉独立的 Ca 爆发调节哺乳动物感觉系统的发育。在未成熟的耳蜗中，内毛细胞 (IHC) 会产生自发的 Ca 动作电位 (AP)，这些 AP 可以由细胞内 Ca 波或非感觉细胞产生。这些 Ca 信号机制中的任一种或两种对于 IHC 成熟的重要程度尚不清楚。我们发现 IHC 中的内在 Ca AP，但不是由 Ca 波引发的那些，调节了静纤毛毛束的成熟和维持。我们使用一种在 IHC 中可逆过表达钾通道 Kir2.1 的小鼠模型（Kir2.1-OE），发现 IHC 膜超极化阻止 IHC 产生内在 Ca AP，但不会阻止由 Ca 波引发的 AP。由于静纤毛的逐渐丢失或融合，内在 Ca AP 的缺失导致在听力开始之前 IHC 中的机械电转导丧失。RNA 测序数据显示，形态发生、肌动蛋白丝为基础的过程和 Rho-GTPase 信号通路相关的途径在 Kir2.1-OE 小鼠中上调。通过在体内操纵 Kir2.1 通道的表达，我们确定了 IHC 中的内在 Ca AP 调节毛束功能的“关键时间窗”。
