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bioRxiv · 10.1101/2023.01.12.523802

Reactivation of the progenitor gene Trim71 enhances the mitotic and hair cell-forming potential of cochlear supporting cells

Li, X.-J.·Morgan, C.·Nadar-Ponniah, P. T.·Kolanus, W.·Doetzlhofer, A.
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Abstract

Cochlear hair cell loss is a leading cause of deafness in humans. Neighboring supporting cells have some capacity to regenerate hair cells. However, their regenerative potential sharply declines as supporting cells undergo maturation (postnatal day 5 in mice). We recently reported that reactivation of the RNA-binding protein LIN28B restores the hair cell-regenerative potential of P5 cochlear supporting cells. Here, we identify the LIN28B target Trim71 as a novel and equally potent enhancer of supporting cell plasticity. TRIM71 is a critical regulator of stem cell behavior and cell reprogramming, however, its role in cell regeneration is poorly understood. Employing an organoid-based assay, we show that TRIM71 reactivation increases the mitotic and hair cell-forming potential of P5 cochlear supporting cells by facilitating their de-differentiation into progenitor-like cells. Our mechanistic work indicates that TRIM71s RNA-binding activity is essential for such ability, and our transcriptomic analysis identifies gene modules that are linked to TRIM71 and LIN28B-mediated supporting cell reprogramming. Furthermore, our study uncovers that the TRIM71-LIN28B target Hmga2 is essential for supporting cell self-renewal and hair cell formation.

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Li, X.-J., Morgan, C., Nadar-Ponniah, P. T., Kolanus, W., Doetzlhofer, A.. 2023-01-13. Reactivation of the progenitor gene Trim71 enhances the mitotic and hair cell-forming potential of cochlear supporting cells. https://doi.org/10.1101/2023.01.12.523802

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