Deletion of Tmtc4 activates the unfolded protein response and causes postnatal hearing loss
Jiang Li, … , Dylan K. Chan, Elliott H. Sherr
Jiang Li, … , Dylan K. Chan, Elliott H. Sherr
Published September 6, 2018
Citation Information: J Clin Invest. 2018;128(11):5150-5162. https://doi.org/10.1172/JCI97498.
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Research Article Cell biology Otology

Deletion of Tmtc4 activates the unfolded protein response and causes postnatal hearing loss

Abstract

Hearing loss is a significant public health concern, affecting over 250 million people worldwide. Both genetic and environmental etiologies are linked to hearing loss, but in many cases the underlying cellular pathophysiology is not well understood, highlighting the importance of further discovery. We found that inactivation of the gene Tmtc4 (transmembrane and tetratricopeptide repeat 4), which was broadly expressed in the mouse cochlea, caused acquired hearing loss in mice. Our data showed Tmtc4 enriched in the endoplasmic reticulum, and that it functioned by regulating Ca2+ dynamics and the unfolded protein response (UPR). Given this genetic linkage of the UPR to hearing loss, we demonstrated a direct link between the more common noise-induced hearing loss (NIHL) and the UPR. These experiments suggested a novel approach to treatment. We demonstrated that the small-molecule UPR and stress response modulator ISRIB (integrated stress response inhibitor), which activates eIF2B, prevented NIHL in a mouse model. Moreover, in an inverse genetic complementation approach, we demonstrated that mice with homozygous inactivation of both Tmtc4 and Chop had less hearing loss than knockout of Tmtc4 alone. This study implicated a novel mechanism for hearing impairment, highlighting a potential treatment approach for a broad range of human hearing loss disorders.

Authors

Jiang Li, Omar Akil, Stephanie L. Rouse, Conor W. McLaughlin, Ian R. Matthews, Lawrence R. Lustig, Dylan K. Chan, Elliott H. Sherr

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Figure 8

UPR in noise-exposed WT mice.

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UPR in noise-exposed WT mice. (A) Eight-week-old WT FVB mice were expose...
(A) Eight-week-old WT FVB mice were exposed to 8–16 kHz octave-band white noise at 106 dB SPL for 120 minutes. Cochleae were removed 2 hours after exposure (Noise) or unexposed (No Noise). mRNA expression of Chop, S-XBP1, BiP, and caspase 3 is presented relative to expression of GAPDH and the average expression levels of control, unexposed cochleae by the 2ΔΔct method. Data represent the mean and SD of 4 (Chop, S-XBP1, and BiP) or 3 (caspase) cochleae in each condition. *P < 0.05; **P < 0.01 by 1-way ANOVA followed by Tukey’s multiple comparisons test. (B) Eight-week-old WT FVB mice were exposed to noise, and ABR thresholds were measured at 1, 7, and 14 days post–noise exposure (PNE). Intraperitoneal injection of ISRIB (n = 11) 2 hours prior to noise exposure attenuated the hearing loss observed in vehicle-injected mice (n = 12). Data represent mean and SD. *P < 0.05 by 1-way ANOVA followed by Tukey’s multiple comparisons test. (C) Whole-mount immunohistochemical staining for Myo7a (green, hair cell marker) and actin (red, phalloidin) demonstrates 3 intact rows of outer hair cells (OHC) in control, nonexposed mice (top); significant OHC loss in mice exposed to noise and treated with vehicle (bottom); and minimal OHC loss in ISRIB-treated mice exposed to noise (middle). Images representative of 5 cochleae for each condition. Original magnification ×60. (D) OHC number was quantified in the mid-basal turn of the cochlea (n = 5 cochleae for each condition, data presented as individual values with median and interquartile range), demonstrating significantly greater OHC loss in vehicle-treated animals exposed to noise (Vehicle), compared with those treated with ISRIB, or non–noise-exposed controls. *P < 0.05 by Mann-Whitney U rank-sum test.