Molecular Structure of the Hair Cell Mechanoelectrical Transduction Complex

Cunningham, Christopher L.; Müller, Ulrich

doi:10.1101/cshperspect.a033167

Cited by 35 publications

(33 citation statements)

References 140 publications

(261 reference statements)

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“…The mechano-electrical transduction (MET) complex of sensory hair cells is an assembly of proteins and lipids that facilitate the conversion of auditory, vestibular and hydrodynamic stimuli into electrical signals. Our current understanding is that the proteins of the MET complex consist of the tip link proteins cadherin 23 (CDH23) and protocadherin 15 (PCDH15) at the upper and lower ends of the tip link respectively (Kazmierczak et al, 2007), the pore-forming subunits transmembrane channel-like proteins TMC1 and TMC2 (Kawashima et al, 2011;Pan et al, 2013Pan et al, , 2018, and the accessory subunits transmembrane inner ear (TMIE) and lipoma HMGIC fusion partner-like 5 (LHFPL5) (Xiong et al, 2012;Zhao et al, 2014;Cunningham and Müller, 2019). How these proteins are correctly localized to the sensory hair bundle and assemble into a functional complex is a fundamental question for understanding the molecular basis of how mechanotransduction occurs.…”

Section: Introductionmentioning

confidence: 99%

The lhfpl5 Ohnologs lhfpl5a and lhfpl5b Are Required for Mechanotransduction in Distinct Populations of Sensory Hair Cells in Zebrafish

Erickson

Pacentine

Venuto

et al. 2020

Front. Mol. Neurosci.

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Hair cells sense and transmit auditory, vestibular, and hydrodynamic information by converting mechanical stimuli into electrical signals. This process of mechano-electrical transduction (MET) requires a mechanically gated channel localized in the apical stereocilia of hair cells. In mice, lipoma HMGIC fusion partner-like 5 (LHFPL5) acts as an auxiliary subunit of the MET channel whose primary role is to correctly localize PCDH15 and TMC1 to the mechanotransduction complex. Zebrafish have two lhfpl5 genes (lhfpl5a and lhfpl5b), but their individual contributions to MET channel assembly and function have not been analyzed. Here we show that the zebrafish lhfpl5 genes are expressed in discrete populations of hair cells: lhfpl5a expression is restricted to auditory and vestibular hair cells in the inner ear, while lhfpl5b expression is specific to hair cells of the lateral line organ. Consequently, lhfpl5a mutants exhibit defects in auditory and vestibular function, while disruption of lhfpl5b affects hair cells only in the lateral line neuromasts. In contrast to previous reports in mice, localization of Tmc1 does not depend upon Lhfpl5 function in either the inner ear or lateral line organ. In both lhfpl5a and lhfpl5b mutants, GFP-tagged Tmc1 and Tmc2b proteins still localize to the stereocilia of hair cells. Using a stably integrated GFP-Lhfpl5a transgene, we show that the tip link cadherins Pcdh15a and Cdh23, along with the Myo7aa motor protein, are required for correct Lhfpl5a localization at the tips of stereocilia. Our work corroborates the evolutionarily conserved co-dependence between Lhfpl5 and Pcdh15, but also reveals novel requirements for Cdh23 and Myo7aa to correctly localize Lhfpl5a. In addition, our data suggest that targeting of Tmc1 and Tmc2b proteins to stereocilia in zebrafish hair cells occurs independently of Lhfpl5 proteins.

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Section: Introductionmentioning

confidence: 99%

The lhfpl5 Ohnologs lhfpl5a and lhfpl5b Are Required for Mechanotransduction in Distinct Populations of Sensory Hair Cells in Zebrafish

Erickson

Pacentine

Venuto

et al. 2020

Front. Mol. Neurosci.

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“…Inner hair cells (IHCs) are the primary sensors of sound-induced vibrations, while outer hair cells (OHCs) are amplifiers of these vibrations (21). Sound stimuli deflect a bundle of stereocilia that project from the apical surface of both IHCs and OHCs and open mechanically gated cation channels, likely TMC1 in a complex with other proteins (22)(23)(24)(25). Stereocilia are anchored into the apical surface of the hair cells with their rootlets embedded in the cuticular plate (26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

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

Katsuno¹,

Belyantseva²,

Cartagena‐Rivera³

et al. 2019

JCI Insight

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“…The tip links are also responsible for transmitting force to the MET complex via interactions with MET complex proteins (Maeda et al, 2014(Maeda et al, , 2017. Components of the MET (or upper tip link density) complex include myosin VIIa, harmonin, and SANS, which localize to the region on the taller stereocilium where the tip link anchors and interact in a large complex with cadherin 23 to regulate MET and tip link tension (Figure 1; Adato et al, 2005b;Grati and Kachar, 2011;Cunningham and Muller, 2019). Cadherin 23 also frequently complexes with myosin-1c and harmonin, which helps to shape and stabilize the stereocilia of the hair bundles (Liu et al, 2012).…”

Section: Interactions Between Ush Proteins In the Inner Earmentioning

confidence: 99%

Usher Syndrome: Genetics and Molecular Links of Hearing Loss and Directions for Therapy

Whatley

Francis

et al. 2020

Front. Genet.

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Usher syndrome (USH) is an autosomal recessive (AR) disorder that permanently and severely affects the senses of hearing, vision, and balance. Three clinically distinct types of USH have been identified, decreasing in severity from Type 1 to 3, with symptoms of sensorineural hearing loss (SNHL), retinitis pigmentosa (RP), and vestibular dysfunction. There are currently nine confirmed and two suspected USH-causative genes, and a further three candidate loci have been mapped. The proteins encoded by these genes form complexes that play critical roles in the development and maintenance of cellular structures within the inner ear and retina, which have minimal capacity for repair or regeneration. In the cochlea, stereocilia are located on the apical surface of inner ear hair cells (HC) and are responsible for transducing mechanical stimuli from sound pressure waves into chemical signals. These signals are then detected by the auditory nerve fibers, transmitted to the brain and interpreted as sound. Disease-causing mutations in USH genes can destabilize the tip links that bind the stereocilia to each other, and cause defects in protein trafficking and stereocilia bundle morphology, thereby inhibiting mechanosensory transduction. This review summarizes the current knowledge on Usher syndrome with a particular emphasis on mutations in USH genes, USH protein structures, and functional analyses in animal models. Currently, there is no cure for USH. However, the genetic therapies that are rapidly developing will benefit from this compilation of detailed genetic information to identify the most effective strategies for restoring functional USH proteins.

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Molecular Structure of the Hair Cell Mechanoelectrical Transduction Complex

Cited by 35 publications

References 140 publications

The lhfpl5 Ohnologs lhfpl5a and lhfpl5b Are Required for Mechanotransduction in Distinct Populations of Sensory Hair Cells in Zebrafish

The lhfpl5 Ohnologs lhfpl5a and lhfpl5b Are Required for Mechanotransduction in Distinct Populations of Sensory Hair Cells in Zebrafish

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

Usher Syndrome: Genetics and Molecular Links of Hearing Loss and Directions for Therapy

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