<i>ybx1</i> acts upstream of <i>atoh1a</i> to promote the rapid regeneration of hair cells in zebrafish lateral-line neuromasts

Like the sensory organs of the human inner ear, the lateral-line neuromasts (NMs) of fish such as the zebrafish (<i>Danio rerio</i>) contain mechanosensory hair cells (HCs) that are surrounded by supporting cells (SCs). A damaged NM can quickly regenerate new HCs by expressing genes such as <i>atoh1a</i>, the master regulator of HC fate, in the SCs at the NM's center. We used the supervised learning algorithm DELAY to infer the early gene-regulatory network for regenerating central SCs and HCs and identified adaptations that promote the rapid regeneration of lateral-line HCs in larval zebrafish. The top hub in the network, <i>Y-box binding protein 1</i> (<i>ybx1</i>), is highly expressed in HC progenitors and young HCs and its protein can recognize DNA-binding motifs in cyprinids' candidate regeneration-responsive promoter element for <i>atoh1a</i>. We showed that NMs from <i>ybx1</i> mutant zebrafish larvae display consistent, regeneration-specific deficits in HC number and initiate both HC regeneration and <i>atoh1a</i> expression 20% slower than in wild-type siblings. By demonstrating that <i>ybx1</i> promotes rapid HC regeneration through early <i>atoh1a</i> upregulation, the results support DELAY's ability to identify key temporal regulators of gene expression.