PUBLICATION
Truncation of the otoferlin transmembrane domain alters the development of hair cells and reduces membrane docking
- Authors
- Manchanda, A., Bonventre, J.A., Bugel, S.M., Chatterjee, P., Tanguay, R., Johnson, C.P.
- ID
- ZDB-PUB-210513-8
- Date
- 2021
- Source
- Molecular biology of the cell 32(14): 1293-1305 (Journal)
- Registered Authors
- Tanguay, Robyn L.
- Keywords
- none
- MeSH Terms
-
- Age Factors
- Animals
- Endocytosis/genetics
- Exocytosis/physiology
- Gene Expression/genetics
- Hair Cells, Auditory/metabolism*
- Humans
- Membrane Proteins/genetics
- Membrane Proteins/metabolism*
- Membrane Proteins/physiology
- Protein Domains/genetics
- Synapses/metabolism
- Zebrafish/metabolism
- PubMed
- 33979209 Full text @ Mol. Biol. Cell
Citation
Manchanda, A., Bonventre, J.A., Bugel, S.M., Chatterjee, P., Tanguay, R., Johnson, C.P. (2021) Truncation of the otoferlin transmembrane domain alters the development of hair cells and reduces membrane docking. Molecular biology of the cell. 32(14):1293-1305.
Abstract
Release of neurotransmitter from sensory hair cells is regulated by otoferlin. Despite the importance of otoferlin in the auditory and vestibular pathways, the functional contributions of the domains of the protein have not been fully characterized. Using a zebrafish model, we investigated a mutant otoferlin with a stop codon at the start of the transmembrane domain. We found that both the phenotype severity and the expression level of mutant otoferlin changed with the age of the zebrafish. At the early developmental timepoint of 72 hours post-fertilization (hpf) low expression of the otoferlin mutant coincided with synaptic ribbon deficiencies, reduced endocytosis, and abnormal transcription of several hair cell genes. As development proceeded, expression of the mutant otoferlin increased, and both synaptic ribbons and hair cell transcript levels resembled wild type. However, hair cell endocytosis deficits and abnormalities in the expression of GABA receptors persisted even after upregulation of mutant otoferlin. Analysis of membrane-reconstituted otoferlin measurements suggest a function for the transmembrane domain in liposome docking. We conclude that that deletion of the transmembrane domain reduces membrane docking, attenuates endocytosis, and results in developmental delay of the hair cell.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping