TY - JOUR
T1 - TRIOBP-5 sculpts stereocilia rootlets and stiffens supporting cells enabling hearing
AU - Katsuno, Tatsuya
AU - Belyantseva, Inna A.
AU - Cartagena-Rivera, Alexander X.
AU - Ohta, Keisuke
AU - Crump, Shawn M.
AU - Petralia, Ronald S.
AU - Ono, Kazuya
AU - Tona, Risa
AU - Imtiaz, Ayesha
AU - Rehman, Atteeq
AU - Kiyonari, Hiroshi
AU - Kaneko, Mari
AU - Wang, Ya Xian
AU - Abe, Takaya
AU - Ikeya, Makoto
AU - Fenollar-Ferrer, Cristina
AU - Riordan, Gavin P.
AU - Wilson, Elisabeth A.
AU - Fitzgerald, Tracy S.
AU - Segawa, Kohei
AU - Omori, Koichi
AU - Ito, Juichi
AU - Frolenkov, Gregory I.
AU - Friedman, Thomas B.
AU - Kitajiri, Shin Ichiro
N1 - Publisher Copyright:
© 2019, American Society for Clinical Investigation.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.128561
DO - 10.1172/jci.insight.128561
M3 - Article
C2 - 31217345
AN - SCOPUS:85070660673
VL - 4
JO - JCI insight
JF - JCI insight
IS - 12
M1 - e128561
ER -
