Deletion of Tricellulin Causes Progressive Hearing Loss Associated with Degeneration of Cochlear Hair Cells.

Toru Kamitani,Hirofumi Sakaguchi,Ryuhei Inamoto,Yuji Yamazaki,Nozomu Mori,Atsushi Tamura,Reitaro Tokumasu,Ai Matsubara,Takenori Miyashita,Yasuo Hisa,Sachiko Tsukita

doi:10.1038/srep18402

Abstract

Tricellulin (also known as MARVELD2) is considered as a central component of tricellular tight junctions and is distributed among various epithelial tissues. Although mutations in the gene encoding tricellulin are known to cause deafness in humans (DFNB49) and mice, the influence of its systemic deletion in vivo remains unknown. When we generated tricellulin-knockout mice (Tric−/−), we found an early-onset rapidly progressive hearing loss associated with the degeneration of hair cells (HCs); however, their body size and overall appearance were normal. Tric−/− mice did not show any morphological change pertaining to other organs such as the gastrointestinal tract, liver, kidney, thyroid gland and heart. The endocochlear potential (EP) was normal in Tric−/− mice, suggesting that the tight junction barrier is maintained in the stria vascularis, where EP is generated. The degeneration of HCs, which occurred after the maturation of EP, was prevented in the culture medium with an ion concentration similar to that of the perilymph. These data demonstrate the specific requirement of tricellulin for maintaining ion homeostasis around cochlear HCs to ensure their survival. The Tric−/− mouse provides a new model for understanding the distinct roles of tricellulin in different epithelial systems as well as in the pathogenesis of DFNB49.

Highlights

Tight junctions (TJs) form close intercellular connections between epithelial cells and maintain epithelial barrier function by regulating paracellular permeability
Because the exon 2 encodes all of the 4 transmembrane domains and its deletion leads to a frameshift mutation, functional tricellulin cannot be produced in Tric−/− mice
Polymerase chain reaction (PCR) analysis demonstrated the disruption of Tric (Fig. S1b), and reverse-transcription PCR (RT-PCR) and western blotting analyses did not detect Tric mRNA or tricellulin, respectively, in the colon tissue extracts of Tric−/− mice on postnatal day (P) 30-P60 (Fig. S1c,d)

Summary

Introduction

Tight junctions (TJs) form close intercellular connections between epithelial cells and maintain epithelial barrier function by regulating paracellular permeability. We demonstrate the effect of the systemic total deficiency in tricellulin by generating Tric-knockout (KO) mice (Tric−/− mice). These mice show hearing loss associated with the degeneration of HCs, which resembles the phenotype of DFNB49 and the Tric-mutated mice, without apparent morphological change in other organs. These results will provide a new basis for understanding the role and redundancy of the tricellulin function

Methods

Results

Conclusion