TRIOBP-5 sculpts stereocilia rootlets and stiffens supporting cells enabling hearing

Katsuno, Tatsuya; Belyantseva, Inna A.; Cartagena‐Rivera, Alexander X.; Ohta, Keisuke; Crump, Shawn M.; Petralia, Ronald S.; Ono, Kazuya; Tona, Risa; Imtiaz, Ayesha; Rehman, Atteeq U.; Kanazawa, Hiroshi; Kaneko, Mari; Wang, Yaxian; Abe, Takaya; Ikeya, Motoji; Fenollar–Ferrer, Cristina; Riordan, Gavin P.; Wilson, Elisabeth A.; Fitzgerald, Tracy S.; Segawa, K.; Omori, Koichi; Ito, Juichi; Frolenkov, Gregory I.; Friedman, Thomas B.

doi:10.1172/jci.insight.128561

Cited by 35 publications

(81 citation statements)

References 49 publications

(96 reference statements)

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“…1B). Because 3-dimensional organization of protruding stereocilia can be confusing in flat-mounts, we labeled stereocilia rootlets at P6 with an antibody against TRIOBP [47]. We found that stereocilia were severely misaligned in Mpdz mutants (Fig.…”

Section: Resultsmentioning

confidence: 99%

Multiple PDZ Domain Protein Maintains Patterning of the Apical Cytoskeleton in Sensory Hair Cells

Jarysta

Tarchini

2021

Preprint

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Sound transduction occurs in the hair bundle, the apical compartment of sensory hair cells in the inner ear. The hair bundle is formed of stereocilia aligned in rows of graded heights. It was previously shown that the GNAI-GPSM2 complex is part of a developmental blueprint that defines the polarized organization of the apical cytoskeleton in hair cells, including stereocilia distribution and elongation. Here we report a novel and critical role for Multiple PDZ domain (MPDZ) protein during apical hair cell morphogenesis. We show that MPDZ is enriched at the hair cell apical membrane, and required there to maintain the proper segregation of apical blueprints proteins, including GNAI-GPSM2. Loss of the blueprint coincides with misaligned stereocilia in Mpdz mutants, and results in permanently misshapen hair bundles. Graded molecular and structural defects along the cochlea can explain the profile of hearing loss in Mpdz mutants, where deficits are most severe at high frequencies.

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Section: Resultsmentioning

confidence: 99%

Multiple PDZ Domain Protein Maintains Patterning of the Apical Cytoskeleton in Sensory Hair Cells

Jarysta

Tarchini

2021

Preprint

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“…Not only the inclusion, but also the skipping, of specific alternative exons during pre-mRNA splicing is important for hearing. Skipping of the longest coding exon of Xirp2 produces a splice form required for maintaining proper stereocilium morphology ( Francis et al, 2015 ), and skipping of a polyadenylation site–containing region of exon 8 of Triobp (which is dependent on alternative splicing) is necessary for maintaining stereocilia rootlets ( Katsuno et al, 2019 ). Several other alternatively spliced exons have been identified in transcripts that encode proteins essential for hearing, although the physiological importance of these exons has not been tested in vivo ( Kollmar et al, 1997 ; Rosenblatt et al, 1997 ; Jones et al, 1999 ; Di Palma et al, 2001 ; Chicka & Strehler, 2003 ; Beisel et al, 2005, 2007 ; Grati et al, 2006 ; Hill et al, 2006 ; Liang et al, 2006 ; Riazuddin et al, 2006 ; Shen et al, 2006 ; Alagramam et al, 2007 ; Rocha-Sanchez et al, 2007 ; Miranda-Rottmann et al, 2010 ; Chen et al, 2011 ; Sakai et al, 2011 ; Västinsalo et al, 2011 ; Narui & Sotomayor, 2018 ; Ranum et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of a transcriptional repressor rescues hearing in a splicing factor–deficient mouse

et al. 2020

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In mechanosensory hair cells (HCs) of the ear, the transcriptional repressor REST is continuously inactivated by alternative splicing of its pre-mRNA. This mechanism of REST inactivation is crucial for hearing in humans and mice. Rest is one of many pre-mRNAs whose alternative splicing is regulated by the splicing factor SRRM4; Srrm4 loss-of-function mutation in mice (Srrm4bv/bv) causes deafness, balance defects, and degeneration of all HC types other than the outer HCs (OHCs). The specific splicing alterations that drive HC degeneration in Srrm4bv/bv mice are unknown, and the mechanism underlying SRRM4-independent survival of OHCs is undefined. Here, we show that transgenic expression of a dominant-negative REST fragment in Srrm4bv/bv mice is sufficient for long-term rescue of hearing, balancing, HCs, alternative splicing of Rest, and expression of REST target genes including the Srrm4 paralog Srrm3. We also show that in HCs, SRRM3 regulates many of the same exons as SRRM4; OHCs are unique among HCs in that they transiently down-regulate Rest transcription as they mature to express Srrm3 independently of SRRM4; and simultaneous SRRM4–SRRM3 deficiency causes complete HC loss by preventing inactivation of REST in all HCs. Thus, our data reveal that REST inactivation is the primary and essential role of SRRM4 in the ear, and that OHCs differ from other HCs in the SRRM4-independent expression of the functionally SRRM4-like splicing factor SRRM3.

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“…TRIOBP-4 and TRI-OBP-5 should function correctly for morphologic and functional durability and continuity, and the mutation of these isoforms in DFNB28 leads to stereociliary fusion which arises from the impairment of actin netstat apical sites of inner ear hairy cells [Park et al, 2018]. In a study conducted with rats, inactivation of TRIOBP-5 and TRI-OBP-4 was shown to cause impairment in the structure of stereocilia bundles in hair cells and also in the supportive cells that have important functions for normal sound transduction in the organ of Corti, facilitating its necessary mechanic flexibility [Katsuno et al, 2019]. Genetic, physiologic, and morphologic studies show that TRI-OBP-5 and TRIOBP-4 play an active role in these sensory and nonsensory cells in the inner ear.…”

Section: Discussionmentioning

confidence: 99%

“…The TRIOBP gene encodes TRIO-and filamentous-actin-binding proteins, which take a significant role in the durability and stiffness of hair cell stereocilia in the cochlea [Kitajiri et al, 2010]. Stereocilia are mechanosensorial structures which are embedded in the apical surface and roots of inner ear hair cells and the cuticular plate [Katsuno et al, 2019]. Soundinduced deflections of the stereocilia bundle change the open probability of the mechanotransduction channel and thereby initiate electrochemical signals that are transmitted via the eighth nerve to the auditory cortex [Zhao and Müller, 2015].…”

Section: Introductionmentioning

confidence: 99%

A New Pathogenic Variant in the TRIOBP Associated with Profound Deafness Is Remediable with Cochlear Implantation

Tekın

Ceulaer²,

Govaerts³

et al. 2020

Audiol Neurotol

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Background and Objectives: A rare type of nonsyndromic autosomal recessive hereditary hearing loss is caused by pathogenic mutations in the TRIOBP gene mostly involving exons 6 and 7. These mutations cause hearing loss originating from dysfunction of sensory inner ear hair cells. Of all the affected siblings, 2 brothers and 1 sister, part of an Afghan family, were referred to our clinic for diagnostic workup and candidacy selection for cochlear implantation (CI). Methods: Molecular analysis showed a homozygous c.1342C > T p. (Arg448*) pathogenic variant in exon 7 of the TRIOBP gene (reference sequence NM_001039141.2) in all 3 affected siblings. Clinical audiometry demonstrated profound sensorineural hearing loss in all 3 affected siblings (2 males and 1 female), and they were implanted unilaterally. Results: One month after activation, the pure-tone averages with the CI processor were between 30 and 23 dBHL. Ten months after the first activation of the implant, open-set speech audiometry test could be performed for the first time in the 2 younger CI recipients (S5 and S9), and they could identify up to a maximum 77% phonemes correctly. The oldest brother (S12) could not yet perform open-set speech audiometry at that moment. Conclusions: Implant outcomes are better with normal inner ear anatomy in general. The earlier congenital patients are implanted, the better their outcomes. Here, we demonstrate both statements are true in a homozygous c.1342C > T p. (Arg448*) pathogenic variant in the TRIOBP gene in all 3 affected siblings.

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TRIOBP-5 sculpts stereocilia rootlets and stiffens supporting cells enabling hearing

Cited by 35 publications

References 49 publications

Multiple PDZ Domain Protein Maintains Patterning of the Apical Cytoskeleton in Sensory Hair Cells

Multiple PDZ Domain Protein Maintains Patterning of the Apical Cytoskeleton in Sensory Hair Cells

Inhibition of a transcriptional repressor rescues hearing in a splicing factor–deficient mouse

A New Pathogenic Variant in the TRIOBP Associated with Profound Deafness Is Remediable with Cochlear Implantation

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