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PROJECT SUMMARY/ABSTRACT
Inner ear hair cells have actin-filled projections on their apical surface that are highly organized in
rows of increasing heights known as hair bundles. These microvilli-like structures are known as
stereocilia, and they have mechano-electrical transduction (MET) channels at their tips. Thus, the
stereocilia bundles are the sites where sound-induced vibrations and head motions are converted into
electrical signals. Velez-Ortega et al. (Elife, 2017) previously showed that the actin cytoskeleton at the
stereocilia tips exhibits MET-dependent remodeling, and that a constant entry of calcium through MET
channels (which are partially open at rest) was crucial to maintain the stability of auditory stereocilia. The
stereocilia actin cytoskeleton is made up of two actin isoforms, beta and gamma, which are produced by
two separate genes. It was previously shown that hair cells can develop stereocilia bundles in the
absence of either beta or gamma actin, but these hair cells quickly degenerate causing hearing loss
(Perrin et al., PLoS Genet, 2010). Therefore, both actin isoforms are required for stereocilia maintenance
throughout the lifetime of vertebrates. Here, we hypothesize that a specific mutation in the gamma actin
gene that leads to progressive hearing loss in humans and mice causes increased MET-dependent
remodeling of the actin cytoskeleton in auditory stereocilia. To test this, Aim 1 will explore MET-dependent
changes to the morphology of stereocilia via scanning electron microscopy after the exposure to MET
channel blockers or an increase in intracellular calcium buffering with BAPTA-AM in auditory hair cells of
mice with the gamma actin mutation and littermate controls. Given that beta and gamma actin exhibit
different rates of polymerization and depolymerization in the presence of calcium (Bergeron et al., J Biol
Chem, 2010), Aim 2 will evaluate MET-dependent changes to the ratio of both actin isoforms in the
stereocilia and cuticular plate of auditory hair cells from the mutant mice and littermate controls using
immunohistochemistry and high-resolution confocal microscopy. Results from this supplement might
uncover the molecular mechanism that triggers stereocilia degeneration in congenital deafness due to
mutations in the gamma actin gene.
Status | Active |
---|---|
Effective start/end date | 6/7/23 → 5/31/28 |
Funding
- National Institute on Deafness & Other Communications
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Projects
- 1 Active
-
Activity-Driven Plasticity of the Hair Cell Cytoskeleton
Velez Ortega, A. C. (PI) & Frolenkov, G. (CoI)
National Institute on Deafness & Other Communications
6/7/23 → 5/31/28
Project: Research project