isl1a Coordinates Onset and Termination of Regeneration of the Zebrafish Lateral Line

Most regeneration studies have focused on identifying genes and pathways that promote regeneration, whereas mechanisms that inhibit regeneration to enforce organ size control and prevent excessive proliferation remain less well defined. Here, we identify isl1a as a dynamically expressed negative regulator of hair cell regeneration in the zebrafish lateral line. isl1a is highly expressed during homeostasis but becomes transiently downregulated following hair cell loss.

Loss of isl1a leads to expansion of support cells and enhanced hair cell differentiation, producing enlarged sensory organs with increased hair cell numbers after injury. Mechanistically, isl1a downregulation increases chromatin accessibility at pro-proliferative loci, including AP-1 transcription factors, and sustains expression of injury- and regeneration-responsive genes. Together, these findings demonstrate that injury-induced downregulation of isl1a promotes the initiation of regeneration, while its subsequent re-expression restricts the duration of the response, thereby fine-tuning hair cell regeneration and maintaining organ size control.