Dynamic patterns of YAP1 expression and cellular localization in the developing and injured utricle

Abstract

The Hippo signaling pathway is a key regulator of tissue development and regeneration. Activation of the Hippo pathway leads to nuclear translocation of the YAP1 transcriptional coactivator, resulting in changes in gene expression and cell cycle entry. Recent studies have demonstrated the nuclear translocation of YAP1 during the development of the sensory organs of the inner ear, but the possible role of YAP1 in sensory regeneration of the inner ear is unclear. The present study characterized the cellular localization of YAP1 in the utricles of mice and chicks, both under normal conditions and after HC injury. During neonatal development, YAP1 expression was observed in the cytoplasm of supporting cells, and was transiently expressed in the cytoplasm of some differentiating hair cells. We also observed temporary nuclear translocation of YAP1 in supporting cells of the mouse utricle after short periods in organotypic culture. However, little or no nuclear translocation of YAP1 was observed in the utricles of neonatal or mature mice after ototoxic injury. In contrast, substantial YAP1 nuclear translocation was observed in the chicken utricle after streptomycin treatment in vitro and in vivo. Together, these data suggest that differences in YAP1 signaling may partially account for the differing regenerative abilities of the avian vs. mammalian inner ear.

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

“…Unfortunately, there are few studies on the role of the Hippo/YAP signaling pathway in auditory organs. Recently, YAP has been reported to be required for HC proliferation and differentiation in the inner ear [67][68][69]. However, whether the Hippo/ YAP signaling pathway is required for HC survival has not been previously investigated.…”

Hearing loss: The final frontier of pharmacology

“…inhibitors and others [29][30][31][32] (Figure 3). Small molecule inhibitors of the enzyme γ-secretase, originally developed for Alzheimer's disease, have been repurposed as potential hearing loss therapeutics due to their ability to modulate Notch signaling, a critical pathway in HC development and non-mammalian regeneration.…”

“…Currently, most research into mammalian HC regeneration places a heavy emphasis on several key signaling pathways upstream of Atoh1 that have been shown to be critical for HC development and regeneration in fish and birds. Some of these pathways and genes include Wnt / β‐catenin , Notch, P27 kip1 , Gfi, MYC, Hippo/YAP , and most recently, epigenetic regulation by histone deacetylase (HDAC) inhibitors and others 29 , 30 , 31 , 32 (Figure 3 ). Small molecule inhibitors of the enzyme γ‐secretase, originally developed for Alzheimer's disease, have been repurposed as potential hearing loss therapeutics due to their ability to modulate Notch signaling, a critical pathway in HC development and non‐mammalian regeneration.…”

Loss of Mst1/2 activity promotes non-mitotic hair cell generation in the neonatal organ of Corti

“…The findings by Rudolf et al suggested that cellular damage overcomes inhibitory Hippo signaling and facilitates regenerative proliferation in non-mammalian utricles, whereas suppressing YAP-TEAD signaling in mammalian utricles contributes to maintaining the proliferative quiescence 26 . The different cellular localizations of YAP may partially account for the regenerative abilities of the utricles in chicks 27 . However, most studies on the Hippo signaling pathway have focused on its function in inhibiting cell proliferation and promoting withdrawal from the cell cycle in the inner ear, and not on its application for promoting HC regeneration.…”