Activated notch causes deafness by promoting a supporting cell phenotype in developing auditory hair cells

Area of Science:

• Developmental Biology
• Neuroscience
• Genetics

Background:

• Sensory cell differentiation in the inner ear is critical for hearing.
• The Notch signaling pathway plays a role in cell fate determination during development.
• SOX2 is a gene implicated in supporting cell development in the inner ear.

Purpose of the Study:

• To investigate if activated Notch signaling can induce a supporting cell fate in developing inner ear sensory cells.
• To determine the functional consequences of Notch activation on hair cell differentiation and hearing.

Main Methods:

• Activated Notch1 receptor (NICD) was expressed in developing hair cells using Gfi1-Cre mice.
• Auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) were measured to assess hearing.
• Histological and molecular markers were used to evaluate hair cell and supporting cell differentiation at various postnatal days.

Main Results:

• Activation of Notch1 in developing hair cells led to profound deafness.
• NICD-expressing hair cells lost hair cell markers and morphology, adopting a supporting cell-like phenotype and upregulating supporting cell markers.
• These Notch-induced effects were not mediated by SOX2, as SOX2 expression alone did not cause these specific changes.

Conclusions:

• Notch signaling inhibits hair cell differentiation and promotes a supporting cell fate in the developing inner ear.
• The observed effects of Notch signaling are unlikely to be mediated through SOX2.
• This study provides insights into the molecular mechanisms governing inner ear sensory cell development and potential therapeutic targets for hearing loss.