Adenomatous Polyposis Coli Protein Deletion in Efferent Olivocochlear Neurons Perturbs Afferent Synaptic Maturation and Reduces the Dynamic Range of Hearing

Hickman, Tyler; Liberman, M. Charles; Jacob, Michele H.

doi:10.1523/jneurosci.4384-14.2015

“…Our results show that striatindeficient mice have a uniform distribution of ribbons that lack the spatial gradient seen in wild-type IHC. Interestingly, a similar aberrant maturation of the synapse is seen in striatin binding protein adenomatous polyposis coli (APC) mutant mice [12]. Taken together, our results present striatin as a novel multifunctional protein that is essential for mammalian hearing.…”

Section: Introductionsupporting

confidence: 65%

“…APC conditional knock-out mice show impaired auditory function, which probably results from aberrant afferent synapse ribbon size gradients. Similarly to the Strn -/mice, the IHCs of the APC knock-out mice show wild-type ribbon numbers but lack the normal ribbon size gradient [12]. As ribbon synapses mediate transmission between IHCs and spiral ganglion neurons (SGNs), our results lead us to propose that striatin, a component of the STRIPAK complex that interacts with the tumor supressor protein APC, regulates interneuronal synapses.…”

Section: Striatin Knockout Mice Display An Aberrant Ribbon Gradientmentioning

confidence: 70%

“…This finding suggests aberrant maturation of the ribbon structure in striatin-deficient mice, which subsequently could affect auditory function. Interestingly, in adenomatous polyposis coli (APC), another striatin-interacting protein, deficient mice, [32,33], ribbon synapses were shown to lack a size gradient towards the modiolar face of the IHCs [12]. APC conditional knock-out mice show impaired auditory function, which probably results from aberrant afferent synapse ribbon size gradients.…”

Section: Striatin Knockout Mice Display An Aberrant Ribbon Gradientmentioning

confidence: 99%

See 1 more Smart Citation

Striatin is required for hearing and affects inner hair cells and ribbon synapses

Ponniah

¹

,

Taiber

²

,

Caspi

³

et al. 2020

Preprint

View full text Add to dashboard Cite

Striatin, a subunit of the serine/threonine phosphatase PP2A, is a core member of the conserved striatin-interacting phosphatase and kinase (STRIPAK) complexes. The protein is expressed in the cell junctions between epithelial cells, which play a role in maintaining cell-cell junctional integrity. Since adhesion is crucial for the function of the mammalian inner ear, we examined the localization and function of striatin in the mouse cochlea. Our results show that in neonatal mice, striatin is specifically expressed in the cell-cell junctions of the inner hair cells, the receptor cells in the mammalian cochlea.Auditory brainstem response measurements of striatin-deficient mice indicated a progressive, high-frequency hearing loss, suggesting that striatin is essential for normal hearing. Moreover, scanning electron micrographs of the organ of Corti revealed a moderate degeneration of the outer hair cells in the middle and basal regions, concordant with the high-frequency hearing loss. Importantly, striatin-deficient mice show aberrant ribbon synapse maturation that may lead to the observed auditory impairment. Together, these results suggest a novel function for striatin in the mammalian auditory system. Medicine Grant for Collaborative Research (RL, RRA). We thank Ana Turchetti-Maia and Kevin Ohlemiller for their advice for EP recordings, Vered Holdengreber for help with electron microscopy, and Ronen Siman-Tov for help with the mice. Author contributions KBA and RRA conceived the project. RAL generated the Striatin knockout mice. PTNP designed and performed the genotyping, dissections of inner ears, ABR, SEM, confocal imaging, Western blots, and quantification of ribbon synapses. MR and ST performed the endocochlear potential experiments. ST and TK-B aided with dissections and SEM imaging analysis. MC and AAD aided with image analysis, experimental design and organizing the data. PTNP, ST, KBA, and RRA wrote the manuscript. KBA and RRA supervised the work.

show abstract

“…Our results show that striatin-deficient mice have a uniform distribution of ribbons that lack the spatial gradient seen in wild-type IHC. Interestingly, a similar aberrant maturation of the synapse is seen in striatin binding protein adenomatous polyposis coli (APC) mutant mice (Hickman et al, 2015). Taken together, our results present striatin as a novel multifunctional protein that is essential for mammalian hearing.…”

Section: Introductionsupporting

confidence: 65%

Striatin Is Required for Hearing and Affects Inner Hair Cells and Ribbon Synapses

Nadar‐Ponniah

¹

,

Taiber

²

,

Caspi

³

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Striatin, a subunit of the serine/threonine phosphatase PP2A, is a core member of the conserved striatin-interacting phosphatase and kinase (STRIPAK) complexes. The protein is expressed in the cell junctions between epithelial cells, which play a role in maintaining cell-cell adhesion. Since the cell junctions are crucial for the function of the mammalian inner ear, we examined the localization and function of striatin in the mouse cochlea. Our results show that in neonatal mice, striatin is specifically expressed in the cell-cell junctions of the inner hair cells, the receptor cells in the mammalian cochlea. Auditory brainstem response measurements of striatin-deficient mice indicated a progressive, high-frequency hearing loss, suggesting that striatin is essential for normal hearing. Moreover, scanning electron micrographs of the organ of Corti revealed a moderate degeneration of the outer hair cells in the middle and basal regions, concordant with the high-frequency hearing loss. Additionally, striatindeficient mice show aberrant ribbon synapse maturation. Loss of the outer hair cells, combined with the aberrant ribbon synapse distribution, may lead to the observed auditory impairment. Together, these results suggest a novel function for striatin in the mammalian auditory system.

show abstract

“…Thirdly, exocytosis elicits large EPSCs to reliably trigger postsynaptic spikes ( Glowatzki and Fuchs, 2002 ; Rutherford et al, 2012 ), and fourthly, exocytosis from IHCs does not require neuronal SNARE proteins ( Nouvian et al, 2011 ). Remarkably, the 10–20 ribbon synapses in each IHC respond differently to the same graded depolarization, a process required to encode different sound intensities, the molecular mechanisms of which are only beginning to be understood ( Merchan-Perez and Liberman, 1996 ; Taberner and Liberman, 2005 ; Frank et al, 2009 ; Meyer et al, 2009 ; Hickman et al, 2015 ; Ohn et al, 2016 ; Reijntjes and Pyott, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Activity-Dependent Phosphorylation by CaMKIIδ Alters the Ca2+ Affinity of the Multi-C2-Domain Protein Otoferlin

Meese

¹

,

Cepeda

²

,

Gahlen

³

et al. 2017

Front. Synaptic Neurosci.

View full text Add to dashboard Cite

Otoferlin is essential for fast Ca2+-triggered transmitter release from auditory inner hair cells (IHCs), playing key roles in synaptic vesicle release, replenishment and retrieval. Dysfunction of otoferlin results in profound prelingual deafness. Despite its crucial role in cochlear synaptic processes, mechanisms regulating otoferlin activity have not been studied to date. Here, we identified Ca2+/calmodulin-dependent serine/threonine kinase II delta (CaMKIIδ) as an otoferlin binding partner by pull-downs from chicken utricles and reassured interaction by a co-immunoprecipitation with heterologously expressed proteins in HEK cells. We confirmed the expression of CaMKIIδ in rodent IHCs by immunohistochemistry and real-time PCR. A proximity ligation assay indicates close proximity of the two proteins in rat IHCs, suggesting that otoferlin and CaMKIIδ also interact in mammalian IHCs. In vitro phosphorylation of otoferlin by CaMKIIδ revealed ten phosphorylation sites, five of which are located within C2-domains. Exchange of serines/threonines at phosphorylated sites into phosphomimetic aspartates reduces the Ca2+ affinity of the recombinant C2F domain 10-fold, and increases the Ca2+ affinity of the C2C domain. Concordantly, we show that phosphorylation of otoferlin and/or its interaction partners are enhanced upon hair cell depolarization and blocked by pharmacological CaMKII inhibition. We therefore propose that otoferlin activity is regulated by CaMKIIδ in IHCs.

show abstract

Adenomatous Polyposis Coli Protein Deletion in Efferent Olivocochlear Neurons Perturbs Afferent Synaptic Maturation and Reduces the Dynamic Range of Hearing

Abstract: Normal hearing requires proper differentiation of afferent ribbon synapses between inner hair cells (IHCs

Cited by 19 publications

References 68 publications

Striatin is required for hearing and affects inner hair cells and ribbon synapses

Striatin is required for hearing and affects inner hair cells and ribbon synapses

Striatin Is Required for Hearing and Affects Inner Hair Cells and Ribbon Synapses

Activity-Dependent Phosphorylation by CaMKIIδ Alters the Ca2+ Affinity of the Multi-C2-Domain Protein Otoferlin

Contact Info

Product

Resources

About