@article{9bc6e98fe42d4a2a8a3106f4ba0e6913,
title = "Cochlear supporting cells require GAS2 for cytoskeletal architecture and hearing",
abstract = "In mammals, sound is detected by mechanosensory hair cells that are activated in response to vibrations at frequency-dependent positions along the cochlear duct. We demonstrate that inner ear supporting cells provide a structural framework for transmitting sound energy through the cochlear partition. Humans and mice with mutations in GAS2, encoding a cytoskeletal regulatory protein, exhibit hearing loss due to disorganization and destabilization of microtubule bundles in pillar and Deiters{\textquoteright} cells, two types of inner ear supporting cells with unique cytoskeletal specializations. Failure to maintain microtubule bundle integrity reduced supporting cell stiffness, which in turn altered cochlear micromechanics in Gas2 mutants. Vibratory responses to sound were measured in cochleae from live mice, revealing defects in the propagation and amplification of the traveling wave in Gas2 mutants. We propose that the microtubule bundling activity of GAS2 imparts supporting cells with mechanical properties for transmitting sound energy through the cochlea.",
keywords = "Gas2, cochlea, cochlear mechanics, cytoskeleton, hearing loss, microtubules, supporting cells",
author = "Tingfang Chen and Rohacek, {Alex M.} and Matthew Caporizzo and Amir Nankali and Smits, {Jeroen J.} and Jaap Oostrik and Lanting, {Cornelis P.} and Erdi K{\"u}c{\"u}k and Christian Gilissen and {van de Kamp}, {Jiddeke M.} and Pennings, {Ronald J.E.} and Rakowiecki, {Staci M.} and Kaestner, {Klaus H.} and Ohlemiller, {Kevin K.} and Oghalai, {John S.} and Hannie Kremer and Prosser, {Benjamin L.} and Epstein, {Douglas J.}",
note = "Funding Information: We thank Dr. Jean Richa and his staff at the Transgenic and Chimeric Mouse Facility (Perelman School of Medicine, University of Pennsylvania) for assistance with transgenic mouse production. We also thank Biao Zuo and Yuri Veklich at the Electron Microscopy Resources Lab (Perelman School of Medicine, University of Pennsylvania) for assistance with TEM and SEM preparations. Use of confocal microscopes (CDB microscopy core, Perelman School of Medicine, University of Pennsylvania) under the supervision of Dr. Andrea Stout, is greatly appreciated. The contributions of Thad{\'e} P.M. Goderie for collection and analysis of human audiometric data, Helger G. IJntema for medical genetic testing of patients, Saskia van der Velde-Visser for EBV transformation and cell culture, and Jailynn Harke for protein co-localization analysis are greatly appreciated. The DOOFNL Consortium consisting of M.F. van Dooren, S.G. Kant, H.H.W. de Gier, E.H. Hoefsloot, M.P. van der Schroeff, L.J.C. Rotteveel, F.G. Ropers, J.C.C. Widdershoven, J.R. Hof, E.K. Vanhoutte, I. Feenstra, H. Kremer, C.P. Lanting, R.J.E. Pennings, H.G. Yntema, R.H. Free and J.S. Klein Wassink-Ruiter, R.J. Stokroos, A.L. Smit, M.J. van den Boogaard, F.A. Ebbens, S.M. Maas, A. Plomp, T.P.M. Goderie, P. Merkus and J. van de Kamp, contributed to the clinical evaluation and medical genetic testing of ∼800 unsolved index cases of hearing loss. This work was funded by grants from the National Institutes of Health, R01 DC006254 (D.J.E.), R01 DC014450, R01 DC013774, and R01 DC017741 (J.S.O.), R01 HL133080 (B.L.P.), the Boucai Innovation Fund in Auditory Genomics (D.J.E.), the Center for Engineering MechanoBiology through a grant from the National Science Foundation's Science and Technology Center program: 15–48571 (B.L.P.), and the Heinsius Houbolt Foundation (R.J.E.P. H.K.). A.M.R was supported by the Predoctoral Training Program in Genetics (T32 GM008216) and an NRSA fellowship F31DC014647. A.N. was supported by T32 DC-00011. T.C. A.M.R. and D.J.E. conceived the study. T.C. A.M.R. S.M.R. and D.J.E. designed and performed mouse molecular, cellular, and genetic studies. M.C. T.C. and B.L.P. performed and analyzed atomic force microscopy (AFM) experiments. A.N. and J.S.O. performed and analyzed VOCTV experiments. K.K.O. performed ABR, DPOAE, and EP recordings. A.M.R. and K.H.K. prepared ESCs for blastocyst injections. J.J.S. J.M.v.d.K. and R.J.E.P performed and supervised the human clinical study. E.K. and C.G. performed bioinformatic analysis of WES data. J.J.S. J.O. and H.K. designed and performed human molecular genetics experiments. T.C. J.S.O. J.J.S. H.K. and D.J.E. wrote the manuscript. All authors analyzed the data, discussed the results, and commented on the manuscript. The authors declare no competing interests. We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as living with a disability. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. Funding Information: We thank Dr. Jean Richa and his staff at the Transgenic and Chimeric Mouse Facility (Perelman School of Medicine, University of Pennsylvania) for assistance with transgenic mouse production. We also thank Biao Zuo and Yuri Veklich at the Electron Microscopy Resources Lab (Perelman School of Medicine, University of Pennsylvania) for assistance with TEM and SEM preparations. Use of confocal microscopes (CDB microscopy core, Perelman School of Medicine, University of Pennsylvania) under the supervision of Dr. Andrea Stout, is greatly appreciated. The contributions of Thad{\'e} P.M. Goderie for collection and analysis of human audiometric data, Helger G. IJntema for medical genetic testing of patients, Saskia van der Velde-Visser for EBV transformation and cell culture, and Jailynn Harke for protein co-localization analysis are greatly appreciated. The DOOFNL Consortium consisting of M.F. van Dooren, S.G. Kant, H.H.W. de Gier, E.H. Hoefsloot, M.P. van der Schroeff, L.J.C. Rotteveel, F.G. Ropers, J.C.C. Widdershoven, J.R. Hof, E.K. Vanhoutte, I. Feenstra, H. Kremer, C.P. Lanting, R.J.E. Pennings, H.G. Yntema, R.H. Free and J.S. Klein Wassink-Ruiter, R.J. Stokroos, A.L. Smit, M.J. van den Boogaard, F.A. Ebbens, S.M. Maas, A. Plomp, T.P.M. Goderie, P. Merkus and J. van de Kamp, contributed to the clinical evaluation and medical genetic testing of ∼800 unsolved index cases of hearing loss. This work was funded by grants from the National Institutes of Health , R01 DC006254 (D.J.E.), R01 DC014450 , R01 DC013774 , and R01 DC017741 (J.S.O.), R01 HL133080 (B.L.P.), the Boucai Innovation Fund in Auditory Genomics (D.J.E.), the Center for Engineering MechanoBiology through a grant from the National Science Foundation {\textquoteright}s Science and Technology Center program: 15–48571 (B.L.P.), and the Heinsius Houbolt Foundation (R.J.E.P., H.K.). A.M.R was supported by the Predoctoral Training Program in Genetics ( T32 GM008216 ) and an NRSA fellowship F31DC014647 . A.N. was supported by T32 DC-00011 . Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = may,
day = "17",
doi = "10.1016/j.devcel.2021.04.017",
language = "English",
volume = "56",
pages = "1526--1540.e7",
journal = "Developmental Cell",
issn = "1534-5807",
number = "10",
}