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TRIOBP-5 sculpts stereocilia rootlets and stiffens supporting cells enabling hearing
Tatsuya Katsuno, … , Thomas B. Friedman, Shin-ichiro Kitajiri
Tatsuya Katsuno, … , Thomas B. Friedman, Shin-ichiro Kitajiri
Published June 20, 2019
Citation Information: JCI Insight. 2019;4(12):e128561. https://doi.org/10.1172/jci.insight.128561.
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Research Article Neuroscience

TRIOBP-5 sculpts stereocilia rootlets and stiffens supporting cells enabling hearing

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Abstract

TRIOBP remodels the cytoskeleton by forming unusually dense F-actin bundles and is implicated in human cancer, schizophrenia, and deafness. Mutations ablating human and mouse TRIOBP-4 and TRIOBP-5 isoforms are associated with profound deafness, as inner ear mechanosensory hair cells degenerate after stereocilia rootlets fail to develop. However, the mechanisms regulating formation of stereocilia rootlets by each TRIOBP isoform remain unknown. Using 3 new Triobp mouse models, we report that TRIOBP-5 is essential for thickening bundles of F-actin in rootlets, establishing their mature dimensions and for stiffening supporting cells of the auditory sensory epithelium. The coiled-coil domains of this isoform are required for reinforcement and maintenance of stereocilia rootlets. A loss of TRIOBP-5 in mouse results in dysmorphic rootlets that are abnormally thin in the cuticular plate but have increased widths and lengths within stereocilia cores, and causes progressive deafness recapitulating the human phenotype. Our study extends the current understanding of TRIOBP isoform–specific functions necessary for life-long hearing, with implications for insight into other TRIOBPopathies.

Authors

Tatsuya Katsuno, Inna A. Belyantseva, Alexander X. Cartagena-Rivera, Keisuke Ohta, Shawn M. Crump, Ronald S. Petralia, Kazuya Ono, Risa Tona, Ayesha Imtiaz, Atteeq Rehman, Hiroshi Kiyonari, Mari Kaneko, Ya-Xian Wang, Takaya Abe, Makoto Ikeya, Cristina Fenollar-Ferrer, Gavin P. Riordan, Elisabeth A. Wilson, Tracy S. Fitzgerald, Kohei Segawa, Koichi Omori, Juichi Ito, Gregory I. Frolenkov, Thomas B. Friedman, Shin-ichiro Kitajiri

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Figure 1

Triobp gene structure, transcripts, protein isoforms, and mutant alleles.

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Triobp gene structure, transcripts, protein isoforms, and mutant allele...
(A) Alternative transcripts of mouse Triobp, the corresponding encoded protein isoforms, and their predicted domains. Locations of the epitopes for 2 antibodies (TRIOBP-4/5 and TRIOBP-5) are depicted with orange and light-blue rectangles, respectively. (B) Drawing of an organ of Corti sensory epithelium segment showing 1 row of inner (IHC) and 3 rows of outer (OHC) hair cells. Inset shows Deiters’ and outer pillar cells supporting an OHC. (C) Mutations of Triobp used to generate 2 genetically different TRIOBP-5–deficient mouse models. TriobpΔEx9-10/ΔEx9-10 has a LacZ cassette replacing exons 9 and 10 of Triobp-5 (schematic 1). The TriobpΔEx8 allele has a LacZ cassette replacing exon 8 (schematic 2) and the TriobpYHB226 allele has a trap cassette with a LacZ insertion in exon 17 (schematic 3). The combination in trans of these 2 Triobp mutations is a compound heterozygote designated TriobpΔEx8/YHB226. Expression of wild-type Triobp isoforms 1, 4, and 5 is indicated to the right of the schematics for each genotype.

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