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

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.

Tricellulin Expression and its Deletion Effects in the Endolymphatic Sac

“…In addition, the morphology of the Tric −/− mouse ES remained normal (Figure 3), with no indication of endolymphatic hydrops. These findings were compatible with the observation that Tric −/− mice show no disturbance in the sense of equilibrium, [10] and the fact that TRIC gene (DFNB49) mutations lead to hearing loss with no obvious vestibular phenotype in humans [9,16,17] .…”

“…Despite the reported barrier dysfunction in the Tric-deficient epithelial cell lines and the severe cochlear dysfunction in Tric −/− mice, we were unable to detect vestibular dysfunction in Tric −/− mice [10] , suggesting that the function of the endolymphatic system can be maintained even without tricellulin. However, the details of the tricellulin expression and the effects of the tricellulin deletion in the ES have not yet been studied.…”

“…Tric is also known as a causative gene for recessive nonsyndromic familial deafness (DFNB49) in humans and mice [9] . We recently investigated Tric-knockout (KO; Tric −/− ) mice, which suffered from early-onset progressive hearing loss associated with the degeneration of hair cells in the cochlea [10] .…”

“…CDB0806K, http://www2.clst.riken.jp/arg/ mutant%20 mice%20list.html) were used, and its generation was previously described by Kamitani et al [10] . The ethics committee of the Animal Care and Use Committees of our institutions approved the study.…”

“…Samples were dehydrated, permeabilized with xylene, mounted, and observed under a light microscope (Olympus BX51; Olympus, Tokyo, Japan). Cochlea samples were made from Tric −/− mice temporal bones on postnatal day 21, paraffin-embedded, and stained with H&E [10] .…”