Wnt5a promotes differentiation and development of adult‐born neurons in the hippocampus by noncanonical Wnt signaling

In the adult hippocampus, new neurons are generated in the dentate gyrus. The Wnt signaling pathway regulates this process, but little is known about the endogenous Wnt ligands involved. We investigated the role of Wnt5a on adult hippocampal neurogenesis. Wnt5a regulates neuronal morphogenesis during embryonic development, and maintains dendritic architecture of pyramidal neurons in the adult hippocampus. Here, we determined that Wnt5a knockdown in the mouse dentate gyrus by lentivirus‐mediated shRNA impaired neuronal differentiation of progenitor cells, and reduced dendritic development of adult‐born neurons. In cultured adult hippocampal progenitors (AHPs), Wnt5a knockdown reduced neuronal differentiation and morphological development of AHP‐derived neurons, whereas treatment with Wnt5a had the opposite effect. Interestingly, no changes in astrocytic differentiation were observed in vivo or in vitro, suggesting that Wnt5a does not affect fate‐commitment. By using specific inhibitors, we determined that Wnt5a signals through CaMKII to induce neurogenesis, and promotes dendritic development of newborn neurons through activating Wnt/JNK and Wnt/CaMKII signaling. Our results indicate Wnt5a as a niche factor in the adult hippocampus that promotes neuronal differentiation and development through activation of noncanonical Wnt signaling pathways. The in vivo knockdown of Wnt5a in the adult mouse dentate gyrus reduced neurogenesis and impaired dendritic arborization of newborn neurons. In addition, in adult hippocampal progenitors (AHPs) isolated from the mouse hippocampus, Wnt5a treatment promoted neuronal differentiation through Wnt/Ca2+ pathway and morphological development of the derived neurons through Wnt/ planar cell polarity (PCP) and Wnt/Ca2+ signaling cascades.