Otoferlin Depletion Results in Abnormal Synaptic Ribbons and Altered Intracellular Calcium Levels in Zebrafish

Abstract The protein otoferlin plays an essential role at the sensory hair cell synapse. Mutations in otoferlin result in deafness and depending on the species, mild to strong vestibular deficits. While studies in mouse models suggest a role for otoferlin in synaptic vesicle exocytosis and endocytos...

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Autores principales:	Aayushi Manchanda, Paroma Chatterjee, Josephine A. Bonventre, Derik E. Haggard, Katie S. Kindt, Robert L. Tanguay, Colin P. Johnson
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/693738f5c51b414bb53355b64b318d18
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spelling	oai:doaj.org-article:693738f5c51b414bb53355b64b318d182021-12-02T15:09:24ZOtoferlin Depletion Results in Abnormal Synaptic Ribbons and Altered Intracellular Calcium Levels in Zebrafish10.1038/s41598-019-50710-22045-2322https://doaj.org/article/693738f5c51b414bb53355b64b318d182019-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-50710-2https://doaj.org/toc/2045-2322Abstract The protein otoferlin plays an essential role at the sensory hair cell synapse. Mutations in otoferlin result in deafness and depending on the species, mild to strong vestibular deficits. While studies in mouse models suggest a role for otoferlin in synaptic vesicle exocytosis and endocytosis, it is unclear whether these functions are conserved across species. To address this question, we characterized the impact of otoferlin depletion in zebrafish larvae and found defects in synaptic vesicle recycling, abnormal synaptic ribbons, and higher resting calcium concentrations in hair cells. We also observed abnormal expression of the calcium binding hair cell genes s100s and parvalbumin, as well as the nogo related proteins rtn4rl2a and rtn4rl2b. Exogenous otoferlin partially restored expression of genes affected by endogenous otoferlin depletion. Our results suggest that in addition to vesicle recycling, depletion of otoferlin disrupts resting calcium levels, alters synaptic ribbon architecture, and perturbs transcription of hair cells specific genes during zebrafish development.Aayushi ManchandaParoma ChatterjeeJosephine A. BonventreDerik E. HaggardKatie S. KindtRobert L. TanguayColin P. JohnsonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-10 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Aayushi Manchanda Paroma Chatterjee Josephine A. Bonventre Derik E. Haggard Katie S. Kindt Robert L. Tanguay Colin P. Johnson Otoferlin Depletion Results in Abnormal Synaptic Ribbons and Altered Intracellular Calcium Levels in Zebrafish
description	Abstract The protein otoferlin plays an essential role at the sensory hair cell synapse. Mutations in otoferlin result in deafness and depending on the species, mild to strong vestibular deficits. While studies in mouse models suggest a role for otoferlin in synaptic vesicle exocytosis and endocytosis, it is unclear whether these functions are conserved across species. To address this question, we characterized the impact of otoferlin depletion in zebrafish larvae and found defects in synaptic vesicle recycling, abnormal synaptic ribbons, and higher resting calcium concentrations in hair cells. We also observed abnormal expression of the calcium binding hair cell genes s100s and parvalbumin, as well as the nogo related proteins rtn4rl2a and rtn4rl2b. Exogenous otoferlin partially restored expression of genes affected by endogenous otoferlin depletion. Our results suggest that in addition to vesicle recycling, depletion of otoferlin disrupts resting calcium levels, alters synaptic ribbon architecture, and perturbs transcription of hair cells specific genes during zebrafish development.
format	article
author	Aayushi Manchanda Paroma Chatterjee Josephine A. Bonventre Derik E. Haggard Katie S. Kindt Robert L. Tanguay Colin P. Johnson
author_facet	Aayushi Manchanda Paroma Chatterjee Josephine A. Bonventre Derik E. Haggard Katie S. Kindt Robert L. Tanguay Colin P. Johnson
author_sort	Aayushi Manchanda
title	Otoferlin Depletion Results in Abnormal Synaptic Ribbons and Altered Intracellular Calcium Levels in Zebrafish
title_short	Otoferlin Depletion Results in Abnormal Synaptic Ribbons and Altered Intracellular Calcium Levels in Zebrafish
title_full	Otoferlin Depletion Results in Abnormal Synaptic Ribbons and Altered Intracellular Calcium Levels in Zebrafish
title_fullStr	Otoferlin Depletion Results in Abnormal Synaptic Ribbons and Altered Intracellular Calcium Levels in Zebrafish
title_full_unstemmed	Otoferlin Depletion Results in Abnormal Synaptic Ribbons and Altered Intracellular Calcium Levels in Zebrafish
title_sort	otoferlin depletion results in abnormal synaptic ribbons and altered intracellular calcium levels in zebrafish
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/693738f5c51b414bb53355b64b318d18
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Otoferlin Depletion Results in Abnormal Synaptic Ribbons and Altered Intracellular Calcium Levels in Zebrafish

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