| 2014 |
TMIE forms a ternary complex with the tip-link component PCDH15 and its binding partner TMHS/LHFPL5 in cochlear hair cells; alternative splicing of the PCDH15 cytoplasmic domain regulates formation of this ternary complex. Homozygous Tmie-null mutation abolishes transducer currents, and subtle Tmie mutations that disrupt interactions with tip links impair transduction, establishing TMIE as an essential component of the mechanotransduction machinery that functionally couples the tip link to the transduction channel. |
Co-immunoprecipitation, null mouse mutant electrophysiology, missense mutations disrupting specific interactions, alternative splicing analysis |
Neuron |
High |
25467981
|
| 2020 |
TMIE is a subunit of the cochlear mechanotransduction channel: TMC1/2 cannot form functional mechanotransduction channels without TMIE; TMIE directly binds TMC1/2, and a TMIE mutation disrupting TMC1/2 binding abolishes mechanotransduction. N-terminal TMIE deletions alter channel response to mechanical force. The C-terminal cytoplasmic domain of TMIE contains charged residues that mediate binding to phospholipids including PIP2; deafness-linked point mutations in this domain disrupt phospholipid binding, sensitize the channel to PIP2 depletion, and alter unitary conductance and ion selectivity. |
Co-immunoprecipitation, in vitro binding assays, site-directed mutagenesis, patch-clamp electrophysiology in hair cells, PIP2 depletion assays, single-channel recordings |
Neuron |
High |
32343945
|
| 2019 |
TMIE is required for targeting and stabilization of TMC1 and TMC2b (MET channel subunits) to hair bundles in zebrafish. In tmie mutants, GFP-tagged Tmc1 and Tmc2b fail to reach the hair bundle; overexpression of Tmie strongly enhances their targeting to stereocilia. Systematic deletion mapping identified the extracellular region and transmembrane domain of Tmie as the critical region required for both mechanosensitivity and Tmc2b-GFP bundle expression. |
GFP-tagged protein localization in tmie zebrafish mutants, overexpression rescue, systematic domain deletion and chimera analysis, functional rescue assays |
PLoS genetics |
High |
30726219
|
| 2025 |
Mouse TMIE potently stimulates TMC1/2 channel activity by modulating their gating in a heterologous expression system. The N-terminal 27 residues of TMIE are dispensable for this regulation, whereas mutation of the predicted palmitoylation sites C76C77 eliminates TMIE stimulation of TMC1/2, indicating a crucial role for the palmitoyl group in regulating TMC1/2 gating. mTMC1/2 + mTMIE reconstitute 18 pS and 24 pS single channels with biophysical and pharmacological properties similar to those of the native MT channel. |
Heterologous expression with Fyn lipidation tag, patch-clamp electrophysiology, site-directed mutagenesis of palmitoylation sites, single-channel recording |
Proceedings of the National Academy of Sciences of the United States of America |
High |
39999170
|
| 2025 |
PIP2 interactions with TMIE mediate slow adaptation of the mechanotransduction channel in mammalian cochlear and vestibular hair cells, independently of myosin motors. Slow adaptation was rescued by exogenous PIP2 when myosin motors were inhibited, indicating the primary importance of PIP2-TMIE interactions. Slow adaptation is independent of myosin VIIa at the upper tip-link end and depends on TMIE-PIP2 interactions at the lower tip-link end. |
Pharmacological inhibition of myosin motors, exogenous PIP2 application, patch-clamp electrophysiology in cochlear and vestibular hair cells, TMIE mutant analysis |
bioRxivpreprint |
Medium |
bio_10.1101_2025.04.01.646713
|
| 2009 |
In zebrafish tmie mutants, hair cells fail to incorporate FM1-43 and fluorophores that traverse transduction channels, and ears lack microphonic potentials in response to vibratory stimuli. Hair bundles lack tip links and insertional plaques, placing TMIE function at the transduction apparatus upstream of or at the MET channel. |
Positional cloning, FM1-43 dye uptake assay, microphonic potential recording, electron microscopy of stereocilia |
Proceedings of the National Academy of Sciences of the United States of America |
Medium |
19934034
|
| 2013 |
In circling (cir/cir) mice lacking tmie, hair cells fail to take up gentamicin, gentamicin-Texas red conjugate, and FM1-43 at postnatal day 3 (before hair-cell degeneration), demonstrating that tmie is required for mechanotransducer channel activity and normal hair cell maturation. |
Gentamicin uptake assay, FM1-43 dye uptake, comparison of cir/cir vs. +/cir mice at P3 |
Comparative medicine |
Medium |
23582420
|
| 2002 |
Loss of function of the mouse Tmie gene results in postnatal defects in cochlear hair cell stereocilia (apical projections critical for mechanotransduction) and profound failure to develop auditory function, establishing that Tmie is required for sensory hair cell integrity and mechanotransduction. |
Positional cloning of spinner (sr) locus, identification of 40 kb deletion and nonsense mutation, auditory brainstem response, scanning electron microscopy of stereocilia |
Human molecular genetics |
High |
12140191
|
| 2011 |
TMIE protein localizes predominantly to the plasma membrane in a stable Tmie-expressing cell line, consistent with its predicted transmembrane topology. |
Immunostaining of stable Myc-tagged Tmie cell line, Western blot |
Laboratory animal research |
Low |
22232643
|
| 2010 |
Tmie protein is expressed prominently in stereocilia bundles of hair cells in early postnatal rat cochlea, then spreads to the hair cell body and organ of Corti cells as development proceeds, suggesting a role in stereocilia maturation and subsequent maintenance. |
Immunohistochemistry with Tmie-specific antibody across postnatal age groups, subcellular localization analysis |
Comparative medicine |
Low |
20819378
|