Retinoic acid receptor assembly dynamics governs dual functions in cochlear organogenesis

Retinoic acid (RA) is a morphogen that contributes to inner ear development. Gain and loss of function experiments have indicated retinoic acid's critical role in cochlear hair cell development. However, the underlying molecular mechanisms are unclear. Here, we hypothesized that RA receptor alpha (RARA) has a dual role in cochlear organogenesis: First, during embryonic development, in the presence of RA, RARA functions as a transcriptional activator that induces prosensory gene expression in progenitor cells and supports differentiation of the organ of Corti; later during postnatal development, when RA is absent, the function of RARA switches, thereby repressing prosensory genes in postnatal hair cells and hindering trans-differentiation into supporting cells. This hypothesis was supported by demonstration that RARA forms a complex with either the coactivator NCOA1 or the corepressor NCOR1 depending on the developmental stage. In addition, modulation of RA levels was found to govern recruitment of the coactivator and corepressor to the RARA complex, and the expression of prosensory genes was validated to depend on RARA complex composition. Together, our results provide insights supporting the potential of harnessing RA signaling to induce prosensory progenitors in stem cell-based strategies for hearing loss.