Roles and action mechanisms of WNT4 in cell differentiation and human diseases: a review

WNT family member 4 (WNT4), which belongs to the conserved WNT protein family, plays an important role in the development and differentiation of many cell types during the embryonic development and adult homeostasis. Increasing evidence has shown that WNT4 is a special ligand that not only activates the β-catenin independent pathway but also acts on β-catenin signaling based on different cellular processes. This article is a summary of the current knowledge about the expression, regulation, and function of WNT4 ligands and their signal pathways in cell differentiation and human disease processes. WNT4 is a promoter in osteogenic differentiation in bone marrow stromal cells (BMSCs) by participating in bone homeostasis regulation in osteoporotic diseases. Non-canonical WNT4 signaling is necessary for metabolic maturation of pancreatic β-cell. WNT4 is also necessary for decidual cell differentiation and decidualization, which plays an important role in preeclampsia. WNT4 promotes neuronal differentiation of neural stem cell and dendritic cell (DC) into conventional type 1 DC (cDC1). Besides, WNT4 mediates myofibroblast differentiation in the skin, kidney, lung, and liver during scarring or fibrosis. On the negative side, WNT4 is highly expressed in cancer tissues, playing a pro-carcinogenic role in many cancer types. This review provides an overview of the progress in elucidating the role of WNT4 signaling pathway components in cell differentiation in adults, which may provide useful clues for the diagnosis, prevention, and therapy of human diseases.