Microtubule and auditory function – an underestimated connection

Bieniussa, L; Jain, Ipsa; Grau, Montserrat Bosch; Juergens, Lukas; Hagen, Rudolf; Janke, Carsten; Rak, Kristen

doi:10.1016/j.semcdb.2022.02.004

Cited by 5 publications

(6 citation statements)

References 161 publications

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“…During inner ear development, each hair cell has a single kinocilium, which is a microtubule‐based organelle. Kinocilia spontaneously degenerate postnatally and are thought to play an important role in the proper orientation of the actin filament‐based stereocilia bundles in mature hair cells (Bieniussa et al , 2023 ). In mature hair cells, microtubules are mainly found in the apical and lateral membrane regions of the cell (Steyger et al , 1989 ).…”

Section: Resultsmentioning

confidence: 99%

Cingulin regulates hair cell cuticular plate morphology and is required for hearing in human and mouse

Zhu,

Huang,

Zhang

et al. 2023

EMBO Mol Med

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Cingulin (CGN) is a cytoskeleton‐associated protein localized at the apical junctions of epithelial cells. CGN interacts with major cytoskeletal filaments and regulates RhoA activity. However, physiological roles of CGN in development and human diseases are currently unknown. Here, we report a multi‐generation family presenting with autosomal dominant non‐syndromic hearing loss (ADNSHL) that co‐segregates with a CGN heterozygous truncating variant, c.3330delG (p.Leu1110Leufs*17). CGN is normally expressed at the apical cell junctions of the organ of Corti, with enriched localization at hair cell cuticular plates and circumferential belts. In mice, the putative disease‐causing mutation results in reduced expression and abnormal subcellular localization of the CGN protein, abolishes its actin polymerization activity, and impairs the normal morphology of hair cell cuticular plates and hair bundles. Hair cell‐specific Cgn knockout leads to high‐frequency hearing loss. Importantly, Cgn mutation knockin mice display noise‐sensitive, progressive hearing loss and outer hair cell degeneration. In summary, we identify CGN c.3330delG as a pathogenic variant for ADNSHL and reveal essential roles of CGN in the maintenance of cochlear hair cell structures and auditory function.

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Section: Resultsmentioning

confidence: 99%

Cingulin regulates hair cell cuticular plate morphology and is required for hearing in human and mouse

Zhu,

Huang,

Zhang

et al. 2023

EMBO Mol Med

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“…However, the con rmation of organoid differentiation is dependent on the presence of the HC marker myosin 7a (Myo7a) along with cell proliferation results 41 . Few studies have con rmed the detailed morphologies of differentiated cells, such as the presence and development of stereocilia (the number of stereocilia increases with differentiation, which leads to cells growing taller and showing distinct morphologies) 42,43 . Accordingly, analyses of cellular characteristics are required, and evaluation of the whole organoid is not su cient.…”

Section: Introductionmentioning

confidence: 99%

Investigation and validation of stereocilia development in homogenic cochlea progenitor cell organoid using bulk and single-cell RNA sequencing analysis

Lee,

Carpena,

Chang

et al. 2024

Preprint

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The hair cell (HC)s exhibit mechanoelectrical transduction that is enabled by stereocilia. Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is known to be involved in the generation of HCs. The stripping method is widely used to differentiate LGR5 progenitor cells (LPC) into inner-ear organoids. However, cells separated via stripping are heterotypic, making it impossible to identify specific cell–cell interactions that affect differentiation. Therefore, methods are needed to differentiate homotypic LPCs. We performed homotypic differentiation of LPCs, and eventually observed HC like cells. However, in further analysis of cellular morphology, immature stereocilia was identified from organoids grown from homotypic LPCs. Using bulk RNA-seq, downregulation of morphogenesis-related genes was identified in organoid by homotypic LPCs. We assessed the effects of an SHH agonist and found that it induced the generation of further differentiated stereocilia. This was confirmed by electron microscopy and significantly heightened expression of stereocilia-related genes (Pls, LMO7, LRBA). Using scRNA-seq, we concentrated on various cochlear markers, including stereocilia formation, to identify cell types that shared a similar developmental trajectory with HCs. Among them, cluster 11 showed robust expression of stereocilia-related genes including Espn, Lhfpl5, Loxhd1, and Tmc1. Further functionality of the cells with this mature stereocilia was confirmed by electrophysiology using multielectrode array.

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“…In the organ of Corti, hair cells are the primary auditory receptor cells [ 5 ]. They are surrounded by supporting cells, including DCs [ 6 , 7 , 8 ] which provide physical and metabolic support to the outer hair cells (OHCs) [ 6 , 9 ]. In addition, they help maintain ion homeostasis in the endolymph via active K + uptake [ 6 , 10 ], and studies have demonstrated that they exhibit functions like glial cells [ 6 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Ca2+ Dynamics of Gap Junction Coupled and Uncoupled Deiters’ Cells in the Organ of Corti in Hearing BALB/c Mice

Moysan,

Fazekas,

Fekete

et al. 2023

IJMS

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ATP, as a paracrine signalling molecule, induces intracellular Ca2+ elevation via the activation of purinergic receptors on the surface of glia-like cochlear supporting cells. These cells, including the Deiters’ cells (DCs), are also coupled by gap junctions that allow the propagation of intercellular Ca2+ waves via diffusion of Ca2+ mobilising second messenger IP3 between neighbouring cells. We have compared the ATP-evoked Ca2+ transients and the effect of two different gap junction (GJ) blockers (octanol and carbenoxolone, CBX) on the Ca2+ transients in DCs located in the apical and middle turns of the hemicochlea preparation of BALB/c mice (P14–19). Octanol had no effect on Ca2+ signalling, while CBX inhibited the ATP response, more prominently in the middle turn. Based on astrocyte models and using our experimental results, we successfully simulated the Ca2+ dynamics in DCs in different cochlear regions. The mathematical model reliably described the Ca2+ transients in the DCs and suggested that the tonotopical differences could originate from differences in purinoceptor and Ca2+ pump expressions and in IP3–Ca2+ release mechanisms. The cochlear turn-dependent effect of CBX might be the result of the differing connexin isoform composition of GJs along the tonotopic axis. The contribution of IP3-mediated Ca2+ signalling inhibition by CBX cannot be excluded.

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Microtubule and auditory function – an underestimated connection

Cited by 5 publications

References 161 publications

Cingulin regulates hair cell cuticular plate morphology and is required for hearing in human and mouse

Cingulin regulates hair cell cuticular plate morphology and is required for hearing in human and mouse

Investigation and validation of stereocilia development in homogenic cochlea progenitor cell organoid using bulk and single-cell RNA sequencing analysis

Ca2+ Dynamics of Gap Junction Coupled and Uncoupled Deiters’ Cells in the Organ of Corti in Hearing BALB/c Mice

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