Human deafness-associated variants alter the dynamics of key molecules in hair cell stereocilia F-actin cores

Miyoshi, Takushi; Belyantseva, Inna A.; Kitajiri, Shin Ichiro; Miyajima, Hiroki; Nishio, Shin‐ya; Usami, Shin Ichi; Kim, Bong Jik; Choi, Byung Yoon; Omori, Koichi; Shroff, Hari; Friedman, Thomas B.

doi:10.1007/s00439-021-02304-0

Cited by 15 publications

(11 citation statements)

References 176 publications

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“…Instead, our molecular results using RNA-seq analysis indicate that the Rho GTPase signaling pathway is disrupted in Sox2 CreER/+ Jag1 fl/fl mice, a pathway commonly involved in actin dynamics. Since the stereocilia are composed mainly of actin, and stereocilia defects are one of the most common causes of deafness [ 54 ], we used SEM to demonstrate that the inner hair cell stereocilia were abnormal in Sox2 CreER/+ Jag1 fl/fl mice, often showing fused and elongated stereocilia. The fact that only the inner hair cell stereocilia are abnormal is consistent with physiological results in JAG1-deficient mice showing raised ABR thresholds while maintaining normal DPOAEs, indicating normal outer hair cell function.…”

Section: Discussionmentioning

confidence: 99%

Deletion of the Notch ligand Jagged1 during cochlear maturation leads to inner hair cell defects and hearing loss

et al. 2022

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The mammalian cochlea is an exceptionally well-organized epithelium composed of hair cells, supporting cells, and innervating neurons. Loss or defects in any of these cell types, particularly the specialized sensory hair cells, leads to deafness. The Notch pathway is known to play a critical role in the decision to become either a hair cell or a supporting cell during embryogenesis; however, little is known about how Notch functions later during cochlear maturation. Uniquely amongst Notch ligands, Jagged1 (JAG1) is localized to supporting cells during cell fate acquisition and continues to be expressed into adulthood. Here, we demonstrate that JAG1 in maturing cochlear supporting cells is essential for normal cochlear function. Specifically, we show that deletion of JAG1 during cochlear maturation disrupts the inner hair cell pathway and leads to a type of deafness clinically similar to auditory neuropathy. Common pathologies associated with disruptions in inner hair cell function, including loss of hair cells, synapses, or auditory neurons, were not observed in JAG1 mutant cochleae. Instead, RNA-seq analysis of JAG1-deficient cochleae identified dysregulation of the Rho GTPase pathway, known to be involved in stereocilia development and maintenance. Interestingly, the overexpression of one of the altered genes, Diaph3, is responsible for autosomal dominant auditory neuropathy-1 (AUNA1) in humans and mice, and is associated with defects in the inner hair cell stereocilia. Strikingly, ultrastructural analyses of JAG1-deleted cochleae revealed stereocilia defects in inner hair cells, including fused and elongated bundles, that were similar to those stereocilia defects reported in AUNA1 mice. Taken together, these data indicate a novel role for Notch signaling in normal hearing development through maintaining stereocilia integrity of the inner hair cells during cochlear maturation.

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Section: Discussionmentioning

confidence: 99%

Deletion of the Notch ligand Jagged1 during cochlear maturation leads to inner hair cell defects and hearing loss

et al. 2022

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“…This mutation partially relieves the autoinhibitory DID-DAD interaction, resulting in a mildly constitutive active molecule [21]. It is likely that this also occurs with other truncation mutations mapping around this site and with the missense mutations in the DID [119,120]. The DIAPH1 gene mouse homolog, mDia1, is expressed in the organ of Corti during and after cochlear maturation, and localizes at the apical junctional complexes between the supporting cells and the hair cells [121].…”

Section: Hearing Lossmentioning

confidence: 99%

Formins in Human Disease

Labat-de-Hoz

Alonso

2021

Cells

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Almost 25 years have passed since a mutation of a formin gene, DIAPH1, was identified as being responsible for a human inherited disorder: a form of sensorineural hearing loss. Since then, our knowledge of the links between formins and disease has deepened considerably. Mutations of DIAPH1 and six other formin genes (DAAM2, DIAPH2, DIAPH3, FMN2, INF2 and FHOD3) have been identified as the genetic cause of a variety of inherited human disorders, including intellectual disability, renal disease, peripheral neuropathy, thrombocytopenia, primary ovarian insufficiency, hearing loss and cardiomyopathy. In addition, alterations in formin genes have been associated with a variety of pathological conditions, including developmental defects affecting the heart, nervous system and kidney, aging-related diseases, and cancer. This review summarizes the most recent discoveries about the involvement of formin alterations in monogenic disorders and other human pathological conditions, especially cancer, with which they have been associated. In vitro results and experiments in modified animal models are discussed. Finally, we outline the directions for future research in this field.

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“…In particular, the development of sensitive and efficient molecular tests to verify the actual impact of the newly identified variants on the function of DRFs will help both in confirming pathogenicity and in understanding phenotype–genotype correlations. In this context, a novel and promising approach has recently been developed, which is based on the use of single-molecule fluorescence microscopy to evaluate the actin elongation activity of mutant DIAPH1 in cultured cells [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…Missense mutations in the GBD and DID domain of DIAPH1 possibly act via a similar gain-of-function mechanism [ 20 , 38 , 39 , 40 , 41 , 42 ]. For instance, single-molecule fluorescence microscopy was recently used to confirm the pathogenicity of one of these mutation (p.A265S, located in the DID domain), suggesting that—in analogy with mutations in the DAD—it also disrupts the autoinhibitory interaction between the two domains [ 43 ].…”

Section: Drf Mutations and Hearing Lossmentioning

confidence: 99%

Role of Cytoskeletal Diaphanous-Related Formins in Hearing Loss

Chiereghin

Robusto

Massa

et al. 2022

Cells

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Hearing relies on the proper functioning of auditory hair cells and on actin-based cytoskeletal structures. Diaphanous-related formins (DRFs) are evolutionarily conserved cytoskeletal proteins that regulate the nucleation of linear unbranched actin filaments. They play key roles during metazoan development, and they seem particularly pivotal for the correct physiology of the reproductive and auditory systems. Indeed, in Drosophila melanogaster, a single diaphanous (dia) gene is present, and mutants show sterility and impaired response to sound. Vertebrates, instead, have three orthologs of the diaphanous gene: DIAPH1, DIAPH2, and DIAPH3. In humans, defects in DIAPH1 and DIAPH3 have been associated with different types of hearing loss. In particular, heterozygous mutations in DIAPH1 are responsible for autosomal dominant deafness with or without thrombocytopenia (DFNA1, MIM #124900), whereas regulatory mutations inducing the overexpression of DIAPH3 cause autosomal dominant auditory neuropathy 1 (AUNA1, MIM #609129). Here, we provide an overview of the expression and function of DRFs in normal hearing and deafness.

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Human deafness-associated variants alter the dynamics of key molecules in hair cell stereocilia F-actin cores

Cited by 15 publications

References 176 publications

Deletion of the Notch ligand Jagged1 during cochlear maturation leads to inner hair cell defects and hearing loss

Deletion of the Notch ligand Jagged1 during cochlear maturation leads to inner hair cell defects and hearing loss

Formins in Human Disease

Role of Cytoskeletal Diaphanous-Related Formins in Hearing Loss

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