Abstract
Current treatments for hearing loss, the most common neurosensory disorder, do not restore perfect hearing. Regeneration of lost organ of Corti hair cells through forced cell cycle re-entry of supporting cells or through manipulation of stem cells, both avenues towards a permanent cure, require a more complete understanding of normal inner ear development, specifically the balance of proliferation and differentiation required to form and to maintain hair cells. Direct successful alterations to the cell cycle result in cell death whereas regulation of upstream genes is insufficient to permanently alter cell cycle dynamics. The Myc gene family is uniquely situated to synergize upstream pathways into downstream cell cycle control. There are three Mycs that are embedded within the Myc/Max/Mad network to regulate proliferation. The function of the two ear expressed Mycs, N-Myc and L-Myc were unknown less than two years ago and their therapeutic potentials remain speculative. In this review, we discuss the roles the Mycs play in the body and what led us to choose them to be our candidate gene for inner ear therapies. We will summarize the recently published work describing the early and late effects of N-Myc and L-Myc on hair cell formation and maintenance. Lastly, we detail the translational significance of our findings and what future work must be performed to make the ultimate hearing aid: the regeneration of the organ of Corti.
Highlights
Hearing Loss Is a Worldwide Problem with No Perfect SolutionHearing loss afflicts over 500 million people worldwide, including half of individuals over the age of 65 and 3 in every 1,000 births totaling 16 million children [1], making hearing loss the most common neurosensory disorder
When Myc binds Myc Associated factor X (Max), the resulting heterodimer creates an architectural scaffold allowing the binding of co-factor TRAP and components of the histone acetyltransferase complexes (HAT), which together bind with the E-box of the promoter regions of the E2Fs, cyclinDs, IDs, and many other Myc regulated genes to promote transcription [113,114]
Pax2 is one of the earliest markers of the otic placode [136], and the Atoh1-Cre transgenic mouse [75], where Atoh1 is necessary for formation of hair cells of the inner ear [26]. These lines were crossed with N-Myc floxed [130] and L-Myc floxed (Dr Eisenman; Jackson Laboratories) mice to assess the function of the two ear expressed Mycs during early inner ear development and later in inner ear hair cells
Summary
Hearing loss afflicts over 500 million people worldwide, including half of individuals over the age of 65 and 3 in every 1,000 births totaling 16 million children [1], making hearing loss the most common neurosensory disorder. In SNHL, sound waves enter the ear canal and are transformed into physical vibrations of normal amplitude; damaged hair cells are unable to respond to the vibrations and fail to stimulate ganglion neurons (Figure 1D). As the fluid waves propagate through the scalae, they cause vibrations of the overlaying basilar membrane This vibration results in a shearing force of organ of Corti hair cells against the tectorial membrane to activate the auditory nerve (A). The best of the current treatments for patients with neurosensory hearing loss are cochlear implants, a prosthesis that is surgically inserted into the scala tympani of the inner ear and stimulates nearby spiral ganglion neuron processes (Figure 1F). Current prostheses are unable to provide a long-WHUPVROXWLRQFDSDEOHRISHUIHFWKHDULQJUHVWRUDWLRQUHOHJDWLQJWKH3ZRUOG¶V EHVWKHDULQJDLGWR regeneration of the damaged or lost organ of Corti [25]
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