MRTF-SRF信号通路调控内耳毛细胞肌动蛋白细胞骨架结构稳态的机制研究

肌动蛋白细胞骨架结构是毛细胞感音功能的结构基础，该结构的异常是感音神经性聋的主要致病因素，但其调控机制尚不清楚。既往研究表明MRTF-SRF信号通路在神经、心血管系统肌动蛋白细胞骨架结构稳态调节中起关键作用。我们研究发现，椭圆囊毛细胞中，Mrtf-b感知胞质肌动蛋白动态变化；Srf毛细胞特异性敲除引起毛细胞纤毛退化，表皮板肌动蛋白网状结构异常，伴严重听力损失。据此提出假说，Srf与Mrtf-b形成转录复合物，调控下游肌动蛋白周转途径相关基因的转录，维持毛细胞肌动蛋白细胞骨架结构。本课题拟利用Srf、Mrtf-b毛细胞特异性敲除小鼠，研究MRTF-SRF信号通路异常状态下，毛细胞肌动蛋白细胞骨架的超微结构及功能，阐明Srf与Mrtf-b的相互作用，以及MRTF-SRF信号通路调节肌动蛋白细胞骨架结构稳态的机制。本研究将为揭示毛细胞肌动蛋白细胞骨架调控机理，感音神经性聋发生机制提供新思路。

The actin cytoskeleton constitutes the structural basis of all hair cell features required for mechanoreceptor function, but less is known about the transcriptional regulation of actin cytoskeleton. The MRTF-SRF circuit has been described in depth as an essential key pathway of cytoskeletal genes involved in actin dynamics and cytoskeletal activity of brain development and cardiovascular system. Our initial studies showed that Mrtf-b shuttles between the cytosol and the nucleus, depending on the ratio of monomeric to filamentous actin in the utricle hair cells. We also found that hair cell specific deletion of Srf causes rapid deterioration of hair cell stereocilia and significantly reduced F-actin density in the cuticular plate, resulting in profound hearing loss. Overall, our current results suggested that Mrtf-b operates as a cofactor to regulate SRF-dependent transcription, and the MRTF-SRF circuit is critical for actin cytoskeleton homeostasis and mechanotransduction function in the hair cell. To address this hypothesis, using Srf and Mrtf-b conditional knockout mice, we will test whether the actin-based cytoskeleton is disrupted in Srf-deficient hair cells and whether Mrtf-b acts as a transcriptional co-factor of Srf in the context of hair cells, and investigate the molecular mechanism of MRTF-SRF signaling pathway important for hair cell maintenance and function, providing insights into the regulation of actin cytoskeleton and the understanding of a broad spectrum of sensorineural hearing loss phenotypes.