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Hearing loss affects ∼10% of adults worldwide. Most sensorineural hearing loss is caused by the progressive loss of mechanosensitive hair cells (HCs) in the cochlea. The molecular mechanisms underlying HC maintenance and loss remain poorly understood. LBH, a transcription co-factor implicated in development, is abundantly expressed in outer hair cells (OHCs). We used Lbh-null mice to identify its role in HCs. Surprisingly, Lbh deletion did not affect differentiation and the early development of HCs, as nascent HCs in Lbh knockout mice had normal looking stereocilia. The stereocilia bundle was mechanosensitive and OHCs exhibited the characteristic electromotility. However, Lbh-null mice displayed progressive hearing loss, with stereocilia bundle degeneration and OHC loss as early as postnatal day 12. RNA-seq analysis showed significant gene enrichment of biological processes related to transcriptional regulation, cell cycle, DNA damage/repair and autophagy in Lbh-null OHCs. In addition, Wnt and Notch pathway-related genes were found to be dysregulated in Lbh-deficient OHCs. Our study implicates, for the first time, loss of LBH function in progressive hearing loss, and demonstrates a critical requirement of LBH in promoting HC survival in adult mice.

Hearing loss affects ~10% of adults worldwide and is irreversible. Most sensorineural hearing loss is caused by progressive loss of mechanosensitive hair cells (HCs) in the cochlea of the inner ear. The molecular mechanisms underlying HC maintenance and loss are largely unknown. Our previous cell-specific transcriptome analysis showed that Limb-Bud-and-Heart (LBH), a transcription co-factor implicated in development, is abundantly expressed in outer hair cells (OHCs). We used Lbh-null mice to identify its role. Surprisingly, Lbh deletion did not affect differentiation and early development of HCs, as nascent HCs in Lbh knockout mice had normal looking stereocilia bundles. Whole-cell recording showed that the stereocilia bundle was mechanosensitive and OHCs exhibited the characteristic electromotility. However, Lbh-null mice displayed progressive hearing loss, with stereocilia bundle degeneration and OHC loss as early as postnatal day 12. Cell-specific RNA-seq and bioinformatic analyses identified Spp1, Six2, Gps2, Ercc6, Snx6 as well as Plscr1, Rarb, Per2, Gmnn and Map3k5 among the top five transcription factors up- or down-regulated in Lbh-null OHCs. Furthermore, this analysis showed significant gene enrichment of biological processes related to transcriptional regulation, cell cycle, DNA damage/repair and autophagy. In addition, Wnt and Notch pathway-related genes were found to be dysregulated in Lbh-deficient OHCs. We speculate that LBH may promote maintenance of HCs and stereocilia bundles by regulating Notch and Wnt signaling activity. Our study implicates, for the first time, loss of LBH function in progressive hearing loss, and demonstrates a critical requirement of LBH in promoting HC survival.

Graphical abstract, Highlights • Chronic nicotine use that replaces tobacco smoking weakens antioxidant defense. • Depletion of glutathione by chronic nicotine delivery may compromise liver health. • Inter-α-trypsin Inhibitor Heavy Chain 3 (Itih3) mRNA correlates with glutathione. • Nicotine and sex interact with Cd44 signaling in regulation of liver glutathione., Cluster of differentiation 44 (Cd44), a hyaluronan receptor, and the secreted hyaluronan-binding protein Inter-α-trypsin Inhibitor Heavy chain 3 (Itih3) play an important role in cancer and oxidative stress. Smoking of tobacco reduces Itih3 in the plasma and activates hyaluronan signaling through Cd44, but the impact of Cd44 on Itih3 expression is unknown. Here, we studied changes induced by the tobacco component nicotine on the glutathione (GSH) antioxidant system and Itih3 gene expression in Cd44 knockout mice. Cd44 deficiency decreased baseline total GSH and oxidized glutathione (GSSG) levels in the liver compared to wildtype mice. However, contrary to wildtype mice, chronic oral nicotine administration (200 μg/ml) failed to further reduce total GSH and GSSG in Cd44 mice. Sex differences with lowered glutathione levels in females was also detectable only in wildtype but not Cd44 knockout mice. Itih3 mRNA levels in the liver and hypothalamus were not affected by nicotine, Cd44 genotype or sex. Nonetheless, the correlation between Itih3 and total GSH levels in the liver (r = 0.42, p

Although the general course of the glossopharyngeal nerve has been established for many years, this nerve is often damaged during head and neck surgeries. Individuals suffering from damage to the g...