Murine Fam65b forms ring-like structures at the base of stereocilia critical for mechanosensory hair cell function

Area of Science:

• Otoacoustic emissions and hair cell biology
• Molecular mechanisms of hearing and deafness
• Cellular structures and their functions

Background:

• Cochlear hair cells are essential for hearing, converting sound vibrations into electrical signals.
• Mutations in the FAM65B gene are linked to hearing loss, but the underlying mechanism remains unclear.
• The precise function of FAM65B within the complex machinery of hair cells is not well understood.

Purpose of the Study:

• To elucidate the molecular mechanism by which FAM65B mutations cause hearing loss.
• To investigate the structural and functional role of FAM65B in the stereocilia of cochlear hair cells.
• To identify FAM65B interacting partners and their role in hair cell mechanotransduction.

Main Methods:

• Biochemical assays to study protein interactions and oligomerization.
• Stochastic optical reconstruction microscopy (STORM) for high-resolution imaging of protein structures.
• Yeast-two-hybrid screening to identify binding partners of Fam65b.
• Analysis of stereocilia development and function in Fam65b-deficient mouse models.

Main Results:

• Fam65b forms ring-like oligomers at the base of stereocilia, crucial for hair cell structure.
• The protein Taperin's dense-core-like structure is dependent on Fam65b.
• Fam65b deficiency impairs stereocilia development, mechanotransduction, and leads to their deterioration.
• RhoC is identified as a binding partner of Fam65b, regulating its oligomerization and function.

Conclusions:

• Fam65b is essential for organizing a critical compartment at the base of stereocilia.
• RhoC interaction and Fam65b oligomerization are vital for hair cell function.
• Disruption of this compartment underlies hearing loss associated with FAM65B mutations.