The Myc Road to Hearing Restoration

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.

An Integrated Perspective of Evolution and Development: From Genes to Function to Ear, Lateral Line and Electroreception

“…Sox2 and Neurog1 are in negative feedback, which allows proliferation and initiates differentiation. This differentiation interacts with retinoblastoma (Rb), Hes/Hey and IDs to regulate the cyclin-dependent kinases ( CDKs ), cross-react with e-proteins and define whether a cell cycle is progressing [ 98 , 100 , 105 , 106 ]. In the end, continuation depends on either knocking out Rb to continue proliferation or upregulating of Sox2 to jumpstart proliferation [ 107 , 108 ].…”

“…In addition to this cross-interaction, the spinal cord is further expanded by another bHLH set of genes, the Hes/Her genes [ 53 , 160 ] and the ID genes [ 9 , 99 , 161 ]. Starting with Sox2 expression, the neurosensory precursor cells are self-renewing and are driven by the Hes, ID and Myc genes to enhance proliferation [ 105 ]. The expansion changes by an oscillation to interact with Hes/Ascl1 , for example.…”

Rescue from early-onset hearing loss in a mouse model lacking the cyclin-dependent kinase inhibitor p19Ink4d

“…In particular, the absence of mammalian inner ear sensory hair cell (HC) regenerative capabilities drove researchers towards gathering clues on their differentiation and maintenance; this would help in the future design of approaches for enhancing HCs' maintenance power and eventually inducing their regeneration. 1 Mechanisms responsible for cell cycle exit, epithelium patterning and post-mitotic cell cycle arrest of maturing and mature HCs have been a challenging field of focus in auditory research, and the information so far gathered is rather scarce. 2 For example, in a mouse line lacking cyclin-dependent kinase inhibitor p19 Ink4d (p19), Chen et al 3 have shown that p19 does not influence mouse embryonic stereotyped patterning of cochlea zone of non-proliferating cells into the organ of Corti that is composed of a mosaic of sensory HCs and supporting cells occurring around embryonic days 15.5 and 17.5.…”