FGF22 promotes generation of ribbon synapses through downregulating MEF2D

Area of Science:

• Neuroscience
• Otolaryngology
• Molecular Biology

Background:

• Cochlear ribbon synapses are crucial for auditory signal transmission.
• Damage to these synapses from noise or aging causes sensorineural hearing loss.
• Altered levels of FGF22 and MEF2D were observed in an ototoxicity model with impaired ribbon synapses.

Purpose of the Study:

• To investigate the regulatory mechanisms of ribbon synapse impairment involving FGF22 and MEF2D.
• To elucidate the signaling pathway connecting FGF22, MEF2D, and cochlear function.
• To identify potential therapeutic targets for hearing loss.

Main Methods:

• Adeno-associated virus (AAV) vectors were used to manipulate FGF22, MEF2D, and calcineurin (CalN) expression in cultured mouse hair cells.
• Experiments involved assessing the suppressive relationship between FGF22 and MEF2D.
• Cochlear infusions of AAV vectors were performed in a mouse model to evaluate functional impacts.

Main Results:

• FGF22 was identified as a suppressor of MEF2D.
• FGF22 signaling appears to increase intracellular calcium, activating CalN, which then inhibits MEF2D.
• Reducing FGF22 (shFGF22) led to increased MEF2D, fewer ribbon synapses, and impaired hearing, effects reversed by inhibiting MEF2D (shMEF2D).

Conclusions:

• Ribbon synapse function is regulated by a FGF22/calcium/CalN/MEF2D signaling pathway.
• This pathway represents a novel therapeutic target for addressing sensorineural hearing loss.
• Understanding this molecular mechanism is key to developing future hearing loss treatments.