A free intravesicular C-terminal of otoferlin is essential for synaptic vesicle docking and fusion at auditory inner hair cell ribbon synapses.
Progress in Neurobiology. 2024-09-01; 240: 102658
DOI: 10.1016/j.pneurobio.2024.102658
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Dulon D(1), de Monvel JB(2), Plion B(3), Mallet A(3), Petit C(3), Condamine S(4), Bouleau Y(4), Safieddine S(5).
Author information:
(1)Institut Pasteur, Université Paris Cité, Inserm U06, Institut de
l’Audition, Paris, France; Bordeaux Neurocampus, Université de
Bordeaux, Bordeaux 33076, France. Electronic address: .
(2)Institut Pasteur, Université Paris Cité, Inserm U06, Institut de
l’Audition, Paris, France. Electronic address: .
(3)Institut Pasteur, Université Paris Cité, Inserm U06, Institut de
l’Audition, Paris, France.
(4)Institut Pasteur, Université Paris Cité, Inserm U06, Institut de
l’Audition, Paris, France; Bordeaux Neurocampus, Université de
Bordeaux, Bordeaux 33076, France.
(5)Institut Pasteur, Université Paris Cité, Inserm U06, Institut de
l’Audition, Paris, France; Centre National de la Recherche Scientifique, Paris,
France. Electronic address: .
Our understanding of how otoferlin, the major calcium sensor in inner hair cells
(IHCs) synaptic transmission, contributes to the overall dynamics of synaptic
vesicle (SV) trafficking remains limited. To address this question, we generated
a knock-in mouse model expressing an otoferlin-GFP protein, where GFP was fused
to its C-terminal transmembrane domain. Similar to the wild type protein, the
GFP-tagged otoferlin showed normal expression and was associated with IHC SV.
Surprisingly, while the heterozygote Otof+/GFP mice exhibited a normal hearing
function, homozygote OtofGFP/GFP mice were profoundly deaf attributed to severe
reduction in SV exocytosis. Fluorescence recovery after photobleaching revealed
a markedly increased mobile fraction of the otof-GFP-associated SV in Otof
GFP/GFP IHCs. Correspondingly, 3D-electron tomographic of the ribbon synapses
indicated a reduced density of SV attached to the ribbon active zone.
Collectively, these results indicate that otoferlin requires a free
intravesicular C-terminal end for normal SV docking and fusion.
Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.pneurobio.2024.102658
PMID: 39103114
Conflict of interest statement: Declaration of Competing Interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper.