miR-34/449 regulates the differentiation of ciliated cells in the oviduct via the Wnt/beita-catenin signaling pathway

The oviduct epithelium comprises two major cell types (secretory cells and ciliated cells). It plays a functional role in the transportation of gametes and serves as a site for fertilization. However, despite its importance, little is known about the underlying mechanisms governing oviductal epithelial homeostasis between secretory cells and ciliated cells. Previously, it was reported that ablation of the miR-34/449 cluster results in a reduction in ciliated cells, disrupting the balance between the secretory cells and ciliated cells; yet, the mechanism governing the imbalance between the two cell types remains exclusive. In this study, we found that miR-34b/c and miR-449a/b/c are expressed in ciliated cells and secretory cells of the oviductal epithelium, positively correlating with the ciliated cell number. Using the miR-34b/c-/-, miR-449 -/- double knockout (miR-dKO) mouse model, we found that adult female miR-dKO mice were infertile, owing to reduced ciliated cells and increased secretory cells, which hindered oocyte pickup. Transcriptomic analysis revealed Wnt signaling over-activation in miR-dKO oviductal epithelia, with Dvl2 as a target gene of miR-34/449. The aberrant ciliated cell differentiation was completely rescued with the treatment of the Wnt pathway signal inhibitors as well as partially rescued with knockdown of Dvl2, using the oviductal epithelial organoid culture model. Taking all this into account, we discovered that ablation of miR-34/449 led to hyperactivation of the Wnt/beita-catenin signaling pathway, which promoted the proliferation of secretory cells and impaired the differentiation of ciliated cells, thus resulting in infertility in the mice. This study revealed a novel mechanism for miR-34/449 in oviductal ciliated cell differentiation and oviductal epithelium homeostasis through the Wnt/beita-catenin signaling pathway.