Loss of Zbtb20 disrupts cochlear supporting cell differentiation and maturation and extends the postnatal hair cell regenerative window in mice.

Cochlear hair cell (HC) loss is a leading cause of hearing loss in humans. HCs can be generated from adjacent supporting cells (SCs); however, this regenerative capacity is lost after the onset of hearing. Using Emx2Cre Zbtb20 knockout mice, we show that ZBTB20 deficiency delays cell-cycle exit, differentiation, and maturation of cochlear SCs. Transcriptomic analysis of postnatal cochlear sensory epithelia indicates that ZBTB20 loss postpones the downregulation of progenitor genes, including Sox11 and Hmga2, and delays activation of a maturation-specific gene program. Additionally, experiments with cochlear organoid and organotypic explant models, reveal that prolonged, and to a lesser extent acute, ZBTB20 loss increases the mitotic and HC-regenerative potential of cochlear SCs. Transcriptomic profiling shows that acute ZBTB20 loss upregulates the midkine receptor Ptprz1, and further studies show that exogenous midkine, similar to ZBTB20 loss, promotes cell-cycle reentry and proliferation in cochlear organoid cultures.