Deletion of Tmtc4 activates the unfolded protein response and causes postnatal hearing loss
Jiang Li, Omar Akil, Stephanie L. Rouse, Conor W. McLaughlin, Ian R. Matthews, Lawrence R. Lustig, Dylan K. Chan, Elliott H. Sherr
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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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 3

Expression of Tmtc4 and its isoforms in mice.

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Expression of Tmtc4 and its isoforms in mice. In heterozygous Tmtc4-KO m...
In heterozygous Tmtc4-KO mice, β-gal expression is driven in the KO allele by the Tmtc4 promoter. β-gal expression is seen broadly in the cochlea, particularly in the stria vascularis (SV), spiral ligament (SLg), and organ of Corti (OC), with less expression noted in the spiral limbus (SLm) and spiral ganglion (SG). (B) In a magnified view of A, the organ of Corti contains inner (IHC) and outer (OHC) hair cells, as well as supporting cells (pillar cells [PC], Dieter’s cells [DC], and Claudius cells [CC]), with robust labelling. (C) WT control mice, in which Tmtc4 promoter–driven β-gal expression is not present, shows no β-gal antibody labeling, demonstrating that the broad labelling seen in A and B is specific.