The miR-34/449 clusters regulate the differentiation of ciliated cells in the oviduct via the Wnt/β-catenin signaling pathway.

BACKGROUND: The oviduct (or fallopian tube) plays a functional role in the transportation of gametes and early-stage embryos, serving as a site for fertilization. Any aberrations from the normal functioning of fallopian tube epithelium may lead to diseases, including but not limited to infertility, ectopic pregnancy, and carcinoma. However, little is known about the mechanisms governing oviductal epithelial homeostasis between secretory cells and ciliated cells by miRNAs. RESULTS: In this study, we found that the expression levels of miR-34b/c and miR-449a/b/c were positively correlated with the number of ciliated cells. 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/β-catenin signaling over-activation in the oviductal epithelium of the miR-dKO mice, with Dvl2 as a target of miR-34/449. The aberrant ciliated cell differentiation was completely rescued with the treatment of the Wnt/β-catenin signaling pathway inhibitors and partially rescued with the knockdown of Dvl2, using the oviductal epithelial organoid culture model. CONCLUSIONS: In summary, we discovered that ablation of miR-34/449 led to hyperactivation of the Wnt/β-catenin signaling pathway, which resulted in the differentiation impairment of ciliated cells, thus resulting in infertility in the mice. This study revealed a novel mechanism describing how miR-34/449 affects oviductal ciliated cell differentiation and oviductal epithelial homeostasis through the Wnt/β-catenin signaling pathway and finally affects fertility.