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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 3

Progressive hearing loss in TRIOBP-5–deficient mice.

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Progressive hearing loss in TRIOBP-5–deficient mice.
(A) Average auditor...
(A) Average auditory brainstem response (ABR) thresholds in TriobpΔEx8/+ heterozygous control mice (gray/black) and TriobpΔEx8/YHB226 compound heterozygous TRIOBP-5–deficient mice (shades of green). (B) Average ABR thresholds in Triobp+/+ (wild-type) and TriobpΔEx9-10/+ heterozygous controls (gray/black) and in TriobpΔEx9-10/ΔEx9-10 mice (shades of blue). ABRs were measured at 4, 8, and 12 weeks postnatally at frequencies of 8, 16, and 32 kHz. When no response was detected at a maximum stimulus level of 90 dB SPL, the threshold was assigned as 100 dB SPL (dashed line in A and B). Error bars indicate SD. (C) SEM images of P43 mouse IHC and OHC stereocilia bundles from normal-hearing TriobpΔEx8/+ heterozygotes (left) and from deaf TriobpΔEx8/YHB226 (right) compound heterozygotes. (D) SEM images of mouse P35 stereocilia bundles of wild-type and TriobpΔEx9-10/ΔEx9-10 OHCs and IHCs. Note fusion of stereocilia of mutant IHC and loss of stereocilia from longer row in OHC hair bundle. Scale bars: 2 μm in C and right panels in D, and 5 μm in D, left panel.

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