Abstract
Objectives:
Sensorineural hearing loss (SNHL) is a common problem of our generation and has increased over the past decades. Normal function of inner ear hair cells is crucial for hearing. In mammals, inner ear hair cells cannot regenerate after damage. A single transcription factor, Atoh1, is sufficient and essential for the formation of a hair cell from a sensory progenitor cell. Two early otic transcription factors, Pax2 and Sox2, play a role in activation of Atoh1 and hair cell fate in inner ear progenitors. The aims of the study were (1) understand molecular basics of hair cell development; (2) learn about the underlying mechanisms that can regenerate hair cells from stem cells.
Methods:
Biochemical analysis (chromatin-immunoprecipitation and luciferase assays) of the Atoh1 regulatory region responsible for hair cell fate and the upstream regulators Sox2 and Pax2. In vitro stem cell assay (cell culture) to induce hair cell fate from inner ear progenitors by manipulation of Sox2 and Pax2.
Results:
In hair cell progenitors, Sox2 and Pax2 are needed simultaneously in the same cell, where they co-bind to the regulatory region of Atoh1 to activate Atoh1 expression. Activation of Atoh1 transcription leads to a hair cell phenotype.
Conclusions:
We show for the first time that Pax2 and Sox2 have a role in cell fate specification and that both factors act together to activate Atoh1 expression. Our data provide a mechanism that could be used in the future to regenerate hair cells after trauma in the inner ear.