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.

Details

Title
Otoferlin Depletion Results in Abnormal Synaptic Ribbons and Altered Intracellular Calcium Levels in Zebrafish
Author
Manchanda, Aayushi 1 ; Chatterjee, Paroma 1 ; Bonventre, Josephine A 2 ; Haggard, Derik E 3 ; Kindt, Katie S 4   VIAFID ORCID Logo  ; Tanguay, Robert L 5 ; Johnson, Colin P 6 

1  Molecular and Cellular Biology Program, Oregon State University, Corvallis, Oregon, USA 
2  Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon, USA 
3  Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon, USA 
4  National Institute of Deafness and Other Communication Disorders (NIDCD), NIH, Maryland, USA 
5  Molecular and Cellular Biology Program, Oregon State University, Corvallis, Oregon, USA; Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon, USA 
6  Molecular and Cellular Biology Program, Oregon State University, Corvallis, Oregon, USA; Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon, USA 
Pages
1-10
Publication year
2019
Publication date
Oct 2019
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-019-50710-2
ProQuest document ID
2300608933
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.