title: Tricellulin deficiency affects tight junction architecture and cochlear hair cells.
abstract: The two compositionally distinct extracellular cochlear fluids, endolymph and perilymph, are separated by tight junctions that outline the scala media and reticular lamina. Mutations in TRIC (also known as MARVELD2), which encodes a tricellular tight junction protein known as tricellulin, lead to nonsyndromic hearing loss (DFNB49). We generated a knockin mouse that carries a mutation orthologous to the TRIC coding mutation linked to DFNB49 hearing loss in humans. Tricellulin was absent from the tricellular junctions in the inner ear epithelia of the mutant animals, which developed rapidly progressing hearing loss accompanied by loss of mechanosensory cochlear hair cells, while the endocochlear potential and paracellular permeability of a biotin-based tracer in the stria vascularis were unaltered. Freeze-fracture electron microscopy revealed disruption of the strands of intramembrane particles connecting bicellular and tricellular junctions in the inner ear epithelia of tricellulin-deficient mice. These ultrastructural changes may selectively affect the paracellular permeability of ions or small molecules, resulting in a toxic microenvironment for cochlear hair cells. Consistent with this hypothesis, hair cell loss was rescued in tricellulin-deficient mice when generation of normal endolymph was inhibited by a concomitant deletion of the transcription factor, Pou3f4. Finally, comprehensive phenotypic screening showed a broader pathological phenotype in the mutant mice, which highlights the non-redundant roles played by tricellulin.
authors: Laboratory of Molecular Genetics, Division of Pediatric Otolaryngology / Head and Neck Surgery, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio 45229, USA.
authors: Gowri
authors: G
authors: Nayak
authors: Sue I
authors: SI
authors: Lee
authors: Rizwan
authors: R
authors: Yousaf
authors: Stephanie E
authors: SE
authors: Edelmann
authors: Claire
authors: C
authors: Trincot
authors: Christina M
authors: CM
authors: Van Itallie
authors: Ghanshyam P
authors: GP
authors: Sinha
authors: Maria
authors: M
authors: Rafeeq
authors: Sherri M
authors: SM
authors: Jones
authors: Inna A
authors: IA
authors: Belyantseva
authors: James M
authors: JM
authors: Anderson
authors: Andrew
authors: A
authors: Forge
authors: Gregory I
authors: GI
authors: Frolenkov
authors: Saima
authors: S
authors: Riazuddin
mesh_terms: D000818:Animals; D005260:Female; D018072:Hair Cells, Auditory, Outer / Q000378:metabolism*; D034381:Hearing Loss / Q000378:metabolism* / Q000473:pathology; D062794:MARVEL Domain Containing 2 Protein / Q000172:deficiency* / Q000235:genetics; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008855:Microscopy, Electron, Scanning; D020125:Mutation, Missense; D009925:Organ of Corti / Q000473:pathology; D013316:Stria Vascularis / Q000378:metabolism / Q000473:pathology; D019108:Tight Junctions / Q000378:metabolism*; D014722:Vestibule, Labyrinth / Q000378:metabolism / Q000473:pathology
chemical_list: D062794:MARVEL Domain Containing 2 Protein; C508309:Marveld2 protein, mouse
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