gms | German Medical Science

Introduction: Sensorineural hearing loss (SNHL) is a common problem of our generation and has increased over the last 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 essential for the formation of a hair cell from progenitors, but not much is known about the regulation of Atoh1 expression. Two transcription factors, Pax2 and Sox2, play an important role during early inner ear morphogenesis.

Neonatal organ of Corti tissue was cultured as stem cells. Differentiated stem cells were analyzed with antibodies for progenitor, hair cell and supporting cell markers.

Methods: Immunoprecipitiation for Pax2 and Sox2 or Chromatin-Immunoprecipitiation were performed. Luciferase assays with the Atoh1-enhancer were used for functional studies. Hair cell regeneration was assessed after stimulation or inhibition of Pax2 and Sox2.

Results: Our data suggests synergistic effects for Pax2 and Sox2 at the time of hair cell formation. Only mouse inner ear progenitors that co-express Pax2 and Sox2 in vitro, will differentiate into hair cells. Overexpression of Sox2 or Pax2 alone slightly increases Atoh1 expression and the number of hair cells in vitro, whereas co-transfection of both leads to robust up-regulation of Atoh1 and increased numbers of hair cells. Both transcription factors are needed simultaneously in the same cell, where they co-bind to the regulatory region of Atoh1 as a dimer to activate Atoh1 expression.

Conclusion: 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 provides a mechanism that could be used in the future to regenerate hair cells after trauma in the inner ear.

Supported by: NIH, NIDCD, DRF

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