A regulatory axis for tonotopic MYO7A expression in cochlear hair cells

Area of Science:

• Genetics
• Neuroscience
• Otolaryngology

Background:

• The MYO7A gene is critical for inner ear hair cell function and its mutations cause hearing loss.
• Distinct MYO7A isoforms are expressed in cochlear hair cells, with specific spatial and cell-type patterns.
• Understanding the regulation of these isoforms is key to deciphering cochlear development and function.

Purpose of the Study:

• To identify regulatory elements controlling the expression of distinct MYO7A isoforms in the cochlea.
• To investigate the functional role of a novel intronic cis-regulatory element, EnhancerA, in MYO7A expression and cochlear function.

Main Methods:

• Gene editing (EnhancerA deletion) in mouse models.
• Analysis of MYO7A protein expression patterns using immunohistochemistry.
• Assessment of hair cell structure and function via electron microscopy and electrophysiology.
• Identification of transcription factors interacting with EnhancerA.

Main Results:

• Deletion of EnhancerA resulted in tonotopically varied MYO7A protein reduction.
• Loss of EnhancerA function disrupted hair bundle morphogenesis and mechanotransduction in outer hair cells.
• EnhancerA deletion led to progressive hair cell degeneration and hearing impairment.
• The transcription factor SIX2 was identified as a potential regulator of MYO7A-N isoform via EnhancerA.

Conclusions:

• EnhancerA is an essential cis-regulatory element for tonotopically graded MYO7A expression in the cochlea.
• A cis-trans regulatory axis involving EnhancerA and SIX2 is critical for isoform-specific MYO7A expression and cochlear function.
• Dysregulation of this axis contributes to hearing loss, highlighting potential therapeutic targets for Usher syndrome and deafness.