The integrity of cochlear hair cells is established and maintained through the localization of Dia1 at apical junctional complexes and stereocilia.

Cell Death & Disease
Yuzuru NinoyuTakehiko Ueyama

Abstract

Dia1, which belongs to the diaphanous-related formin family, influences a variety of cellular processes through straight actin elongation activity. Recently, novel DIA1 mutants such as p.R1213X (p.R1204X) and p.A265S, have been reported to cause an autosomal dominant sensorineural hearing loss (DFNA1). Additionally, active DIA1 mutants induce progressive hearing loss in a gain-of-function manner. However, the subcellular localization and pathological function of DIA1(R1213X/R1204X) remains unknown. In the present study, we demonstrated the localization of endogenous Dia1 and the constitutively active DIA1 mutant in the cochlea, using transgenic mice expressing FLAG-tagged DIA1(R1204X) (DIA1-TG). Endogenous Dia1 and the DIA1 mutant were regionally expressed at the organ of Corti and the spiral ganglion from early life; alongside cochlear maturation, they became localized at the apical junctional complexes (AJCs) between hair cells (HCs) and supporting cells (SCs). To investigate HC vulnerability in the DIA1-TG mice, we exposed 4-week-old mice to moderate noise, which induced temporary threshold shifts with cochlear synaptopathy and ultrastructural changes in stereocilia 4 weeks post noise exposure. Furthermore, we established a ...Continue Reading

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Methods Mentioned

BETA
transgenic
scanning electron microscopy
transmission electron microscopy
scanning
PCR
electrophoresis
confocal microscopy

Key Resources (RRID) Mentioned

AB_399431
AB_2336883
AB_1196615
AB_398167
AB_10680247
AB_2533147
AB_262044
AB_2256751
AB_444319
AB_10015251

Software Mentioned

BioSigRP
Prism
ZEN
GraphPad
Image J

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