Drep1, a Potential Mediator of miR-137, Modulates Yorkie-Driven Overgrowth in Drosophila

The Hippo–Yorkie (Yki) signaling pathway is a conserved regulator of tissue growth, and its dysregulation leads to excessive growth and tumorigenesis. Although several microRNAs (miRNAs) have been implicated in Hippo pathway regulation, how they modulate Yki activity in vivo remains incompletely understood. Here, we identify miR-137 as a suppressor of Yki-driven overgrowth in a Drosophila model. A functional miRNA screen revealed that miR-137 overexpression markedly suppresses Yki-induced eye overgrowth, whereas inhibition of miR-137 enhances eye overgrowth phenotypes. Through bioinformatic prediction and genetic screening, we identified Drep1 as a candidate downstream factor associated with miR-137 function. RNAi-mediated depletion of Drep1 phenocopies the suppressive effects of miR-137, whereas Drep1 overexpression enhances Yki-driven tissue overgrowth and proliferation. Consistent with these phenotypes, miR-137 overexpression or Drep1 depletion reduces the expression of canonical Yki target genes, including Diap1 and Expanded, indicating decreased Yki transcriptional output. Importantly, Drep1 knockdown was associated with reduced Yki immunostaining in a complementary wing-disk context, suggesting a potential link between Drep1 and Yki-associated signaling. Consistent with this, miR-137 also reduced the expression of ICAD, the mammalian homolog of Drep1, providing preliminary evidence that miR-137 may regulate ICAD expression in mammalian cells. Together, these findings support a potential regulatory relationship between miR-137 and Drep1 that modulates Yki-driven eye overgrowth and reveal an additional layer of Hippo pathway regulation in vivo.