ABSTRACT
More than 80% of all cases of deafness are related to the death or degeneration of cochlear hair cells and the associated spiral ganglion neurons, and a lack of regeneration of these cells leads to permanent hearing loss. Therefore, the regeneration of lost hair cells is an important goal for the treatment of deafness. Atoh1 is a basic helix-loop-helix (bHLH) transcription factor that is critical in both the development and regeneration of cochlear hair cells. Atoh1 is transcriptionally regulated by several signaling pathways, including Notch and Wnt signalings. At the post-translational level, it is regulated through the ubiquitin-proteasome pathway. In vitro and in vivo studies have revealed that manipulation of these signaling pathways not only controls development, but also leads to the regeneration of cochlear hair cells after damage. Recent progress toward understanding the signaling networks involved in hair cell development and regeneration has led to the development of new strategies to replace lost hair cells. This review focuses on our current understanding of the signaling pathways that regulate Atoh1 in the cochlea.
ABSTRACT
More than 80% of all cases of deafness are related to the death or degeneration of cochlear hair cells and the associated spiral ganglion neurons, and a lack of regeneration of these cells leads to permanent hearing loss. Therefore, the regeneration of lost hair cells is an important goal for the treatment of deafness. Atoh1 is a basic helix-loop-helix (bHLH) transcription factor that is critical in both the development and regeneration of cochlear hair cells. Atoh1 is transcriptionally regulated by several signaling pathways, including Notch and Wnt signalings. At the post-translational level, it is regulated through the ubiquitin-proteasome pathway. In vitro and in vivo studies have revealed that manipulation of these signaling pathways not only controls development, but also leads to the regeneration of cochlear hair cells after damage. Recent progress toward understanding the signaling networks involved in hair cell development and regeneration has led to the development of new strategies to replace lost hair cells. This review focuses on our current understanding of the signaling pathways that regulate Atoh1 in the cochlea.
Subject(s)
Humans , Basic Helix-Loop-Helix Transcription Factors/physiology , Cell Differentiation , Cochlea/physiology , Hair Cells, Auditory/physiology , Hearing Loss/etiology , Proteasome Endopeptidase Complex/physiology , Signal Transduction/physiology , Transcription Factors/physiology , Ubiquitin/metabolism , Wnt Signaling Pathway , beta Catenin/physiologyABSTRACT
Hearing impairment has become one of the most common sensory disabilities. The World Health Organization (WHO) estimates that 466 million people were living with disabling hearing loss in 2018, and that number could rise to 900 million by 2050. Conductive hearing loss, which predominantly involves the sound-transmitting route of the outer and middle ear, has been well handled by antibiotics and surgery. However, sensorineural hearing loss, which involves the inner ear and structures further within the auditory pathway, has very limited biological treatment options (current treatment options include only hearing amplification and cochlear implants). Part of the reason for the paucity of therapeutics is due to the complexity of the auditory system and the limited regenerative ability of the hearing sensory cells, hair cells, and connected nerve.