Retinoic acid signaling mediates hair cell regeneration by repressing p27kip and sox2 in supporting cells

摘要

Hair cell damage, caused by various insults, results in hearing loss in humans, one of the major health problems nowadays. In mammals damaged hair cells cannot regenerate, whereas lower vertebrates have retained the ability to replace them by inducing cell proliferation of supporting cells and/or their transdifferentiation. Retinoic Acid (RA) has been implicated in several organs regeneration but its role in hair cell regeneration is unknown. A combination of gene expression profiling, functional assays and cell-lineage tracing experiments allows us to highlight the importance of the RA pathway in hair cell regeneration in zebrafish. Regeneration is impaired upon blockade of the RA pathway in both the inner ear and lateral line systems together with a reduction of supporting cell proliferation. Moreover, the expression of RA pathway components is induced during hair cell regeneration, confirming the activation of the pathway. Finally, we demonstrate that RA is critical for downregulating p27kip and sox2 in supporting cells, allowing them to re-enter the cell cycle. This pivotal role of RA could be relevant in the development of future therapeutic strategies