The Rho GTPase Cell Division Cycle 42 Regulates Stereocilia Development in Cochlear Hair Cells

Du, Haibo; Zhou, Hao; Sun, Yi-Xiao; Zhai, Xiaoyan; Chen, Zhengjun; Wang, Yanfei; Xu, Zhigang

doi:10.3389/fcell.2021.765559

Cited by 3 publications

(3 citation statements)

References 52 publications

(66 reference statements)

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“…Previously it has been shown that members of the Rho GTPase family play an essential role in cochlear hair cell stereocilia formation and maintenance. Specifically, loss or dysregulation of the Rho GTPases RAC1 [ 57 ], CDC42 [ 58 , 59 ], their activator ARHGEF6 [ 60 ], or their downstream effector PAK1 [ 61 ] leads to deficits in cochlear stereocilia development or maintenance. Interestingly, others have shown PCP dysregulation in hair bundles after Cdc42 deletion in both hair cells and supporting cells, but this was not observed after hair cell-only Cdc42 deletion [ 58 , 62 ].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, others have shown PCP dysregulation in hair bundles after Cdc42 deletion in both hair cells and supporting cells, but this was not observed after hair cell-only Cdc42 deletion [ 58 , 62 ]. Furthermore, recent results from Du et al (2021) demonstrate that CDC42 acts in both a cell-autonomous and non-autonomous manner during stereocilia development [ 59 ]. Specifically, a more severe stereocilia phenotype with additional planar cell polarity (PCP) defects were observed after treatment with a CDC42 inhibitor compared to the stereocilia phenotype observed after hair cell-specific Cdc42 inactivation, indicating involvement of other cells like supporting cells, in Cdc42 -mediated PCP regulation [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, recent results from Du et al (2021) demonstrate that CDC42 acts in both a cell-autonomous and non-autonomous manner during stereocilia development [ 59 ]. Specifically, a more severe stereocilia phenotype with additional planar cell polarity (PCP) defects were observed after treatment with a CDC42 inhibitor compared to the stereocilia phenotype observed after hair cell-specific Cdc42 inactivation, indicating involvement of other cells like supporting cells, in Cdc42 -mediated PCP regulation [ 59 ]. These studies indicate that cochlear supporting cells likely play a role in hair cell stereocilia formation and maintenance.…”

Section: Discussionmentioning

confidence: 99%

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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%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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FCHSD2 is required for stereocilia maintenance in mouse cochlear hair cells

Zhai

Shen

et al. 2022

Journal of Cell Science

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Stereocilia are F-actin-based protrusions on the apical surface of inner ear hair cells, and are indispensable for hearing and balancing perception. Stereocilia of each hair cell are organized into rows of increasing heights, forming a staircase-like pattern. The development and maintenance of stereocilia are tightly regulated, and deficits in this process lead to stereocilia disorganization and hearing loss. Previously, we showed that F-BAR protein FCHSD2 is localized along the stereocilia of cochlear hair cells, and could cooperate with CDC42 to regulate F-actin polymerization and cell protrusion formation in cultured COS-7 cells. In the present work, Fchsd2 knockout mice were established to investigate the role of FCHSD2 in hearing. Our data show that stereocilia maintenance is severely affected in cochlear hair cells of Fchsd2 knockout mice, which leads to progressive hearing loss. Moreover, Fchsd2 knockout mice show increased acoustic vulnerability. Noise exposure causes robust stereocilia degeneration as well as enhanced hearing threshold elevation in Fchsd2 knockout mice. Lastly, Fchsd2/Cdc42 double knockout mice show more severe stereocilia deficits and hearing loss, suggesting that FCHSD2 and CDC42 may cooperatively regulate stereocilia maintenance.

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