Hippo/YAP signaling pathway protects against neomycin-induced hair cell damage in the mouse cochlea

Abstract

The Hippo/Yes-associated protein (YAP) signaling pathway has been shown to be able to maintain organ size and homeostasis by regulating cell proliferation, differentiation, and apoptosis. The abuse of aminoglycosides is one of the main causes of sensorineural hearing loss (SSNHL). However, the role of the Hippo/YAP signaling pathway in cochlear hair cell (HC) damage protection in the auditory field is still unclear. In this study, we used the YAP agonist XMU-MP-1 (XMU) and the inhibitor Verteporfin (VP) to regulate the Hippo/YAP signaling pathway in vitro. We showed that YAP overexpression reduced neomycin-induced HC loss, while downregulated YAP expression increased HC vulnerability after neomycin exposure in vitro. We next found that activation of YAP expression inhibited C-Abl-mediated cell apoptosis, which led to reduced HC loss. Many previous studies have reported that the level of reactive oxygen species (ROS) is significantly increased in cochlear HCs after neomycin exposure. In our study, we also found that YAP overexpression significantly decreased ROS accumulation, while downregulation of YAP expression increased ROS accumulation. In summary, our results demonstrate that the Hippo/YAP signaling pathway plays an important role in reducing HC injury and maintaining auditory function after aminoglycoside exposure. YAP overexpression could protect against neomycin-induced HC loss by inhibiting C-Abl-mediated cell apoptosis and decreasing ROS accumulation, suggesting that YAP could be a novel therapeutic target for aminoglycosides-induced sensorineural hearing loss in the clinic.

Temporal and regulatory dynamics of the inner ear transcriptome during development in mice

“…We identified two downregulated paths A and B that are enriched in neurosensory and inner ear development. The enriched KEGG pathways of TFs in these two paths are related to Hippo signaling and TGFβ signaling (Fig 5e), which play important role in mouse inner ear development (30)(31)(32)(33)(34)(35)(36). In detail, the Hippo signaling pathway can maintain organ size and homeostasis by regulating cell proliferation, differentiation, and apoptosis (31).…”

“…We employed DREM2 to infer transcriptional regulatory network during the inner ear development. Most regulatory events occurred between stage E11.5 and E13.5, indicating this period is pivotal for the transcriptional regulation during the inner ear (30)(31)(32)(33)(34)(35)(36). In detail, the Hippo signaling pathway can maintain organ size and homeostasis by regulating cell proliferation, differentiation, and apoptosis (31).…”

“…In detail, the Hippo signaling pathway can maintain organ size and homeostasis by regulating cell proliferation, differentiation, and apoptosis (31). In vitro experiments showed that the upregulated Hippo signaling pathway reduced hair cell loss, while downregulated Hippo signaling pathway increased hair cell vulnerability in the inner ear (33). The TGFβ signal transduction pathway can mediate the expression of retinoic acid (RA), which regulates cell differentiation and normal patterning (35).…”

Pathological mechanisms of connexin26-related hearing loss: Potassium recycling, ATP-calcium signaling, or energy supply?

“…The lack of nutrients such as glucose affects ATP production, leading to reactive oxygen species (ROS) overload and cell apoptosis ( Wang et al, 2016 ; Fetoni et al, 2018 ). This provides a mechanism to explain the massive loss of OHCs due to their high elevated levels of mitochondrial metabolism, making them more susceptible to intracellular ATP deprivation ( Wang et al, 2022 ). Considering that OHCs in the high-frequency region require more energy, it could not only explain that Cx26 defect model mice with delayed progressive hearing loss that usually start to hearing impairment at the high frequencies but also explain that Cx26-related delayed hearing loss has noise susceptibility and age-related characteristics ( Fetoni et al, 2018 ; Lin et al, 2019 ).…”

Targeted Next-Generation Sequencing Identified Novel Compound Heterozygous Variants in the PTPRQ Gene Causing Autosomal Recessive Hearing Loss in a Chinese Family

“…Hearing loss is the most common sensorineural disorder affecting approximately 6.1% of the world population ( Qian et al, 2020 ; Zhang et al, 2021a ; Fu et al, 2021 ; Lv et al, 2021 ). It is estimated that more than half of the hearing loss cases are attributable to genetic factors ( He et al, 2017 ; Wang et al, 2022 ), while the other half of hearing loss cases could be caused by ototoxic drugs, such as aminoglycosides and anti-tumor drugs, aging, excessive noise exposure, and infections ( Li et al, 2018a ; Li et al, 2018b ; Liu et al, 2019a ; Cheng et al, 2019 ; Han et al, 2020 ; He et al, 2020 ; Zhong et al, 2020 ; Zhou et al, 2020 ; Liu et al, 2021a ; Zhang et al, 2021b ; Guo et al, 2021 ; He et al, 2021 ; Bu et al, 2022 ; Fu et al, 2022 ; Jiang et al, 2022 ). The functions of these hearing loss genes play an essential role in the development and function of hair cells and synaptic transmission of spiral ganglion neurons ( Wang et al, 2017 ; Zhu et al, 2018 ; Cheng et al, 2021 ).…”